Patterns of Single-Gene Inheritance - PowerPoint PPT Presentation

Loading...

PPT – Patterns of Single-Gene Inheritance PowerPoint presentation | free to download - id: 70616c-MWVjM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Patterns of Single-Gene Inheritance

Description:

Title: Molecular-3 Author: Fadel A. Sharif Last modified by: fsharif Created Date: 2/21/2001 10:33:58 PM Document presentation format: (3:4) – PowerPoint PPT presentation

Number of Views:33
Avg rating:3.0/5.0
Slides: 123
Provided by: Fad87
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Patterns of Single-Gene Inheritance


1
Patterns of Single-Gene Inheritance
  • Lecture 3

2
Autosomal Dominant Inheritance
  • More than half of all mendelian disorders are
    inherited as AD traits.
  • The incidence of some autosomal dominant
    disorders is high, e.g., familial
    hypercholesterolemia, myotonic dystrophy,
    Huntington disease, neurofibromatosis, and
    polycystic kidney disease.

3
  • AD disorders are individually much less common,
    in aggregate their total incidence is
    appreciable.
  • The burden of autosomal dominant disorders is
    increased because of their hereditary nature
    they become problems for whole kindreds, often
    through many generations.
  • In some cases, the burden is compounded by social
    difficulties resulting from physical or mental
    disability.

4
  • The risk and severity of dominantly inherited
    disease in the offspring depend on whether one or
    both parents are affected and whether the trait
    is strictly dominant or incompletely dominant.
  • Denoting D as the mutant allele and d as the
    normal allele, matings that produce children with
    an autosomal dominant disease can be between two
    heterozygotes (D/d) for the mutation or, more
    frequently, between a heterozygote for the
    mutation (D/d) and a homozygote for a normal
    allele (d/d)

5
Parental Mating Offspring Risk to Offspring
Affected by unaffected D/d d/d 1/2 D/d, 1/2 d/d 1/2 affected 1/2 unaffected
Affected by affected D/d D/d 1/4 D/D, 1/2 D/d, 1/4 d/d If strictly dominant 3/4 affected 1/4 unaffected
If incompletely dominant 1/2 affected similarly to the parents 1/4 affected more severely than the parents 1/4 unaffected



6
  • Offspring of D/d x d/d are approximately 50 D/d
    and 50 d/d.
  • Each pregnancy is an independent event, not
    governed by the outcome of previous pregnancies.
  • Thus, within a family, the distribution of
    affected and unaffected children may be quite
    different from the theoretical expected ratio of
    11, especially if the sibship is small.

7
A pedigree showing typical inheritance of a form
of progressive sensorineural deafness (DFNA1)
inherited as an autosomal dominant trait.
8
  • Achondroplasia, an AD disorder that often occurs
    as a new mutation.
  • Note small stature with short limbs, large head,
    low nasal bridge, prominent forehead, and lumbar
    lordosis in this typical presentation.

9
  • In medical practice, homozygotes for dominant
    phenotypes are not often seen because matings
    that could produce homozygous offspring are rare.
  • Which mating can produce a D/D homozygote?
  • Practically, only the mating of two heterozygotes
    need be considered because D/D homozygotes are
    very rare and generally too severely affected to
    reproduce (fitness 0).

10
Incompletely Dominant Inheritance
  • Achondroplasia incompletely dominant skeletal
    disorder of short-limbed dwarfism and large head.
  • Most achondroplastics have normal intelligence
    and lead normal lives within their physical
    capabilities.
  • A homozygous child of two heterozygotes is often
    recognizable on clinical grounds alone much more
    severely affected and commonly do not survive the
    immediate postnatal period.

11
  • A pedigree of a mating between two individuals
    heterozygous for the mutation that causes
    achondroplasia. The deceased child, individual
    III-3, was a homozygote and died soon after birth.

12
  • Another example is AD familial hypercholesterolemi
    a, leading to premature coronary heart disease.
  • The rare homozygotes have a more severe disease,
    with an earlier age at onset and much shorter
    life expectancy.

13
Cutaneous xanthomas in a familial
hypercholesterolemia homozygote.
14
New Mutation in Autosomal Dominant Inheritance
  • In typical AD inheritance, every affected person
    in a pedigree has an affected parent, who also
    has an affected parent, and so on as far back as
    the disorder can be traced or until the
    occurrence of an original mutation.
  • This is also true, for X-linked dominant
    pedigrees. In fact, most dominant conditions of
    any medical importance come about not only
    through transmission of the mutant allele but
    also through inheritance of a spontaneous, new
    mutation in a gamete.

15
Relationship Between New Mutation and Fitness in
Autosomal Dominant Disorders
  • Once a new mutation has arisen, its survival in
    the population depends on the fitness of persons
    carrying it.
  • There is an inverse relation between the fitness
    of a given AD disorder and the new mutation.
  • At one extreme are disorders that have a fitness
    of zero, and the disorder is referred to as a
    genetic lethal. Must be due to new mutations.

16
  • The affected individual will appear as an
    isolated case in the pedigree.
  • If the fitness is normal, the disorder is rarely
    the result of fresh mutation and the pedigree is
    likely to show multiple affected individuals.

17
Sex-Limited Phenotype in Autosomal Dominant
Disease
  • AD phenotypes may also demonstrate a sex ratio
    that differs from 11.
  • Extreme divergence of the sex ratio is seen in
    sex-limited phenotypes, in which the defect is
    autosomally transmitted but expressed in only one
    sex.
  • An example is male-limited precocious puberty
    (familial testotoxicosis), an AD disorder in
    which affected boys develop secondary sexual
    characteristics and undergo an adolescent growth
    spurt at about 4 years of age.

18
  • In some families, the defect is in the gene that
    encodes the receptor for luteinizing hormone
    (LCGR) these mutations constitutively activate
    the receptor's signaling action even in the
    absence of its hormone.
  • The defect is not manifested in heterozygous
    females.
  • Although the disease can be transmitted by
    unaffected females, it can also be transmitted
    directly from father to son, showing that it is
    autosomal, not X-linked.

19
  • Males with precocious puberty due to activating
    LCGR mutations have normal fertility, and
    numerous multigeneration pedigrees are known.
  • For disorders in which affected males do not
    reproduce, however, it is not always easy to
    distinguish sex-limited autosomal inheritance
    from X-linkage because the critical evidence,
    absence of male-to-male transmission, cannot be
    provided.
  • In that case, other lines of evidence, especially
    gene mapping to learn whether the responsible
    gene maps to the X chromosome or to an autosome,
    can determine the pattern of inheritance and the
    consequent recurrence risk.

20
Pedigree pattern (part of a much larger pedigree)
of male-limited precocious puberty in the family
of the child shown in Figure 7-14. This autosomal
dominant disorder can be transmitted by affected
males or by unaffected carrier females.
Male-to-male transmission shows that the
inheritance is autosomal, not X-linked. Because
the trait is transmitted through unaffected
carrier females, it cannot be Y-linked.
21
Characteristics of Autosomal Dominant Inheritance
  • The phenotype usually appears in every
    generation, each affected person having an
    affected parent.
  • Exceptions or apparent exceptions (1) cases
    originating from fresh mutations and (2) cases in
    which the disorder is not expressed
    (nonpenetrant) or is expressed only subtly in a
    person who has inherited the responsible mutant
    allele.
  • Any child of an affected parent has a 50 risk of
    inheriting the trait.
  • This is true for most families, in which the
    other parent is phenotypically normal. Wide
    deviation from the expected 11 ratio may occur
    by chance in a single family.

22
  • Phenotypically normal family members do not
    transmit the phenotype to their children.
  • exceptions.
  • Males and females are equally likely to transmit
    the phenotype, to children of either sex. In
    particular, male-to-male transmission can occur,
    and males can have unaffected daughters.
  • A significant proportion of isolated cases are
    due to new mutation. The less the fitness, the
    greater is the proportion due to new mutation.

23
X-LINKED INHERITANCE
  • Phenotypes determined by genes on the X have a
    characteristic sex distribution and a pattern of
    inheritance that is usually easy to identify.
  • Approximately 1100 genes are thought to be
    located on the X chromosome, of which
    approximately 40 are presently known to be
    associated with disease phenotypes

24
  • There are only two possible genotypes in males
    and three in females with respect to a mutant
    allele at an X-linked locus.
  • A male with a mutant allele at an X-linked locus
    is hemizygous for that allele, whereas females
    may be homozygous for either the wild-type or
    mutant allele or may be heterozygous.
  • For example, if XH is the wild-type allele for
    the gene for coagulation factor VIII and a mutant
    allele, Xh, causes hemophilia A, the genotypes
    expected in males and females would be as
    follows

25
Genotypes Phenotypes
Males Hemizygous XH Unaffected
Hemizygous Xh Affected
Females Homozygous XH/XH Unaffected
Heterozygous XH/Xh Unaffected (usually)
Homozygous Xh/Xh Affected



26
X Inactivation, Dosage Compensation, and the
Expression of X-Linked Genes
  • The clinical relevance of X inactivation is
    profound. It leads to females having two cell
    populations, one in which one of the X
    chromosomes is active, the other in which the
    other X chromosome is active.
  • For example, in Duchenne muscular dystrophy,
    female carriers exhibit typical mosaic
    expression, allowing carriers to be identified by
    dystrophin immunostaining.
  • Depending on the pattern of random X inactivation
    of the two X chromosomes, two female
    heterozygotes for an X-linked disease may have
    very different clinical presentations because
    they differ in the proportion of cells that have
    the mutant allele on the active X in a relevant
    tissue (as seen in manifesting heterozygotes).

27
Immunostaining for dystrophin in muscle
specimens. A, A normal female (magnification
480). B, A male with Duchenne muscular
dystrophy (480). C, A carrier female (240).
Staining creates the bright lines seen here
encircling individual muscle fibers. Muscle from
DMD patients lacks dystrophin staining. Muscle
from DMD carriers exhibits both positive and
negative patches of dystrophin immunostaining,
reflecting X inactivation
28
Recessive and Dominant Inheritance of X-Linked
Disorders
  • X-linked "dominant" and "recessive" patterns of
    inheritance are distinguished on the basis of the
    phenotype in heterozygous females. Some X-linked
    phenotypes are consistently expressed in carriers
    (dominant), whereas others usually are not
    (recessive).
  • The difficulty in classifying an X-linked
    disorder as dominant or recessive arises because
    females who are heterozygous for the same mutant
    allele in the same family may or may not
    demonstrate the disease, depending on the pattern
    of random X inactivation and the proportion of
    the cells in pertinent tissues that have the
    mutant allele on the active versus inactive
    chromosome.

29
X-Linked Recessive Inheritance
  • The inheritance of X-linked recessive phenotypes
    follows a well-defined and easily recognized
    pattern.
  • An X-linked recessive mutation is typically
    expressed phenotypically in all males who receive
    it but only in those females who are homozygous
    for the mutation.
  • X-linked recessive disorders are generally
    restricted to males and rarely seen among females
    (except for manifesting heterozygotes).

30
  • Hemophilia A is a classic X-linked recessive
    disorder in which the blood fails to clot
    normally because of a deficiency of factor VIII.
  • The hereditary nature of hemophilia and even its
    pattern of transmission have been recognized
    since ancient times, and the condition became
    known as the "royal hemophilia" because of its
    occurrence among descendants of Britain's Queen
    Victoria, who was a carrier.
  • If a hemophiliac mates with a normal female ?
  • Now assume that a daughter of the affected male
    mates with an unaffected male ?

31
Pedigree pattern demonstrating an X-linked
recessive disorder such as hemophilia A,
transmitted from an affected male through females
to an affected grandson and great-grandson.
32
Homozygous Affected Females
  • Relevant for X-linked color-blindness, a
    relatively common X-linked disorder (an affected
    male x a carrier female).
  • Most X-linked diseases are so rare, unusual for a
    female to be homozygous unless parents are
    consanguineous
  • Affected male x carrier female ?

33
Homozygous affected female
Consanguinity in an X-linked recessive pedigree
for red-green color blindness, resulting in a
homozygous affected female
34
Manifesting Heterozygotes and Unbalanced
Inactivation for X-linked Disease
  • Rare, a female carrier of a recessive X-linked
    allele has phenotypic expression of disease
    manifesting heterozygote.
  • Have been described for many X-linked recessive
    disorders, e.g., color-blindness, hemophilia A
    B, DMD, Wiskott-Aldrich syndrome (an X-linked
    immunodeficiency), etc.
  • Whether a female heterozygote will be a
    manifesting heterozygote depends on a number of
    factors

35
  • First, the fraction of cells in which the
    normal/mutant allele happens to remain active
    (unbalanced or skewed X-inactivation).
  • Second, depending on the disorder in question,
    females can have very different degrees of
    disease penetrance and expression, even if their
    degree of skewed inactivation is the same,
    because of underlying physiological functioning
    of genes e.g.,
  • In Hunter syndrome (iduronate sulfatase
    deficiency), cells with normal allele on active X
    can export enzyme to extracellular space, picked
    up by cells in which mutant allele on active X
    and defect is corrected in those cells

36
  • So, penetrance for Hunter syndrome in
    heterozygous females is extremely low even when
    X-inactivation deviates from expected random
    5050 pattern
  • On the other hand, nearly half of all female
    heterozygotes for fragile-X syndrome show
    developmental abnormalities.
  • In addition to manifesting heterozygotes, the
    opposite pattern of skewed inactivation can also
    occur.

37
  • Characteristics of X-Linked Recessive Inheritance
  • The incidence of the trait is much higher in
    males.
  • Heterozygous females are usually unaffected,
    exception?
  • The gene responsible is transmitted from an
    affected man through all his daughters. Any of
    his daughters' sons has a 50 chance of
    inheriting it.
  • The mutant allele is ordinarily never transmitted
    directly from father to son.
  • The mutant allele may be transmitted through a
    series of carrier females if so, the affected
    males in a kindred are related through females.
  • A significant proportion of isolated cases are
    due to new mutation.

38
X-linked Dominant Inheritance
  • Regularly expressed in heterozygotes
  • No male-to-male transmission
  • For a fully penetrant XD pedigree, all daughters
    and none of sons of affected males are affected.
  • Pattern of inheritance through female is no
    different from AD.
  • The expression is usually milder in females, who
    are almost always heterozygotes. Thus, most XD
    disorders are incompletely dominant.
  • Only a few genetic disorders are classified as
    XD.

39
  • E.g., X-linked hypophosphatemic rickets (a.k.a.
    vitamin D-resistant rickets)
  • Defective gene product is one of the
    endopeptidases that activate or degrade a variety
    of peptide hormones
  • Both sexes are affected but, serum phosphate
    level is less depressed and rickets less severe
    in heterozgous females.

40
Pedigree pattern demonstrating X-linked dominant
inheritance
41
X-linked Dominant Disorders with Male Lethality
  • Some rare genetic defects expressed exclusively
    or almost exclusively in females appear to be XD
    lethal in males before birth
  • Typical pedigrees transmission by affected
    female ? affected daughters, normal daughters,
    normal sons in equal proportions (111)
  • Rett syndrome meets criteria for an XD that is
    usually lethal in hemizygous males. The syndrome
    is characterized by normal prenatal and neonatal
    growth and development, followed by rapid onset
    of neurological symptoms and loss of milestones
    between 6 and 18 months of age.

42
Rett syndrome cont.
  • Children become spastic and ataxic, develop
    autistic features and irritable behavior with
    outbursts of crying, and demonstrate
    characteristic purposeless wringing or flapping
    movements of hands and arms.
  • Head growth slows and microcephaly develops.
    Seizures are common (50)
  • Surprisingly, mental deterioration stops after a
    few years and the patients can then survive for
    many decades with a stable but severe
    neurological disability.
  • Most cases caused by spontaneous mutations in an
    X-linked MECP2 gene encoding methyl CpG binding
    protein 2. ? Thought to reflect abnormalities in
    regulation of genes in developing brain.

43
Typical appearance and hand posture of girls with
Rett syndrome
44
Rett syndrome cont.
  • Males who survive with the syndrome usually have
    two X chromosomes (as in 47,XXY or in a
    46,X,der(X) male with the male determining SRY
    gene translocated to an X) or are mosaic for a
    mutation that is absent in most of their cells
  • There are a few apparently unaffected women who
    have given birth to more than one child with Rett
    syndrome. ? X-inactivation pattern in a
    heterozygous female. ? Germline mosaic ?

45
Pedigree pattern demonstrating an X-linked
dominant disorder, lethal in males during the
prenatal period.
46
Characteristics of X-Linked Dominant Inheritance
  • Affected males with normal mates have no affected
    sons and no normal daughters.
  • Both male and female offspring of a heterozygous
    female have a 50 risk of inheriting the
    phenotype. The pedigree pattern is similar to
    that seen with autosomal dominant inheritance.
  • Affected females are about twice as common as
    affected males, but affected females typically
    have milder (although variable) expression of the
    phenotype.

47
New Mutation in X-Linked Disorders
  • In males, genes for X-linked disorders are
    exposed to selection that is complete for some
    disorders, partial for others, and absent for
    still others, depending on the fitness of the
    genotype.
  • Patients with hemophilia have only about 70 as
    many offspring as unaffected males do that is,
    the fitness of affected males is about 0.70.
  • Selection against mutant alleles is more dramatic
    for X-linked disorders such as DMD. DMD is
    currently a genetic lethal because affected males
    usually fail to reproduce. It may, of course, be
    transmitted by carrier females, who themselves
    rarely show any clinical manifestation of the
    disease.
  • New mutations constitute a significant fraction
    of isolated cases of many X-linked diseases. When
    patients are affected with a severe X-linked
    recessive disease, such as DMD, they cannot
    reproduce (i.e., selection is complete), and
    therefore the mutant alleles they carry are lost
    from the population. Because the incidence of DMD
    is not changing, mutant alleles lost through
    failure of the affected males to reproduce are
    continually replaced by new mutations.

48
PSEUDOAUTOSOMAL INHERITANCE
  • Pseudoautosomal inheritance describes the
    inheritance pattern seen with genes in the
    pseudoautosomal region.
  • Alleles for genes in the pseudoautosomal region
    can show male-to-male transmission, and therefore
    mimic autosomal inheritance, because they can
    cross over from the X to the Y during male
    gametogenesis and be passed on from a father to
    his male offspring.

49
  • Dyschondrosteosis, a dominantly inherited
    skeletal dysplasia with disproportionate short
    stature and deformity of the forearm, is an
    example of a pseudoautosomal condition inherited
    in a dominant manner.
  • A greater prevalence of the disease was seen in
    females as compared with males, suggesting an
    X-linked dominant disorder, but the presence of
    male-to-male transmission clearly ruled out
    strict X-linked inheritance.
  • Mutations in the SHOX gene encoding a
    homeodomain-containing transcription factor have
    been found responsible for this condition.
  • SHOX is located in the pseudoautosomal region on
    Xp and Yp and escapes X inactivation.

50
Figure 7-22 Pedigree showing inheritance of
dyschondrosteosis due to mutations in a
pseudoautosomal gene on the X and Y chromosomes.
The arrow shows a male who inherited the trait on
his Y chromosome from his father. His father,
however, inherited the trait on his X chromosome
from his mother
51
MOSAICISM
  • Mosaicism is the presence in an individual or a
    tissue of at least two cell lines that differ
    genetically but are derived from a single zygote.
  • Mosaicism due to X inactivation is a well-known
    phenomenon.
  • More generally, mutations arising in a single
    cell in either prenatal or postnatal life can
    give rise to mosaicism.

52
  • Mosaicism for numerical or structural
    abnormalities of chromosomes is a clinically
    important phenomenon, and somatic mutation is
    recognized as a major contributor to many types
    of cancer.
  • Mosaicism for mutations in single genes, in
    either somatic or germline cells, explains a
    number of unusual clinical observations, such as
    segmental neurofibromatosis, in which skin
    manifestations are not uniform and occur in a
    patchy distribution, and the recurrence of
    osteogenesis imperfecta, a highly penetrant
    autosomal dominant disease, in two or more
    children born to unaffected parents.

53
  • The population of cells that carry a mutation in
    a mosaic individual could theoretically be
    present in some tissues of the body but not in
    the gametes (pure somatic mosaicism), be
    restricted to the gamete lineage only and nowhere
    else (pure germline mosaicism), or be present in
    both somatic lineages and the germline, depending
    on when the mutation occurred in embryological
    development.
  • Whether mosaicism for a mutation involves only
    somatic tissues, the germline, or both depends on
    whether during embryogenesis the mutation
    occurred before or after the separation of
    germline cells from somatic cells.

54
  • If before, both somatic and germline cell lines
    would be mosaic and the mutation could be
    transmitted to the offspring as well as being
    expressed somatically in mosaic form.
  • Thus, e.g., if a mutation were to occur in a
    germline precursor cell, a proportion of the
    gametes would carry the mutation.
  • There are about 30 mitotic divisions in the cells
    of the germline before meiosis in the female and
    several hundred in the male, allowing ample
    opportunity for mutations to occur during the
    mitotic stages of gamete development.

55
Schematic presentation of mitotic cell divisions.
A mutation occurring during cell proliferation,
in somatic cells or during gametogenesis, leads
to a proportion of cells carrying the
mutation-that is, to either somatic or germline
mosaicism.
56
  • Determining whether mosaicism for a mutation is
    present only in the germline or only in somatic
    tissues may be difficult because failure to find
    a mutation in a subset of cells from a readily
    accessible somatic tissue (such as peripheral
    white blood cells, skin, or buccal cells) does
    not ensure that the mutation is not present
    elsewhere in the body, including the germline.
  • Characterizing the extent of somatic mosaicism is
    made more difficult when the mutant allele in a
    mosaic fetus occurs exclusively in the
    extraembryonic tissues (i.e., the placenta) and
    is not present in the fetus itself.

57
Somatic Mosaicism
  • A mutation affecting morphogenesis and occurring
    during embryonic development might be manifested
    as a segmental or patchy abnormality, depending
    on the stage at which the mutation occurred and
    the lineage of the somatic cell in which it
    originated.
  • For example, NF1 is sometimes segmental,
    affecting only one part of the body. Segmental
    NF1 is caused by mosaicism for a mutation that
    occurred after conception. In such cases, the
    patient has normal parents, but if he or she has
    an affected child, the child's phenotype is
    typical for NF1, that is, not segmental.

58
Germline Mosaicism
  • There are well-documented examples where parents
    who are phenotypically normal and test negative
    for being carriers have more than one child
    affected with a highly penetrant autosomal
    dominant or X-linked disorder.
  • Such unusual pedigrees can be explained by
    germline mosaicism. Germline mosaicism is well
    documented in as many as 6 of severe, lethal
    forms of the AD osteogenesis imperfecta, in which
    mutations in type I collagen genes lead to
    abnormal collagen, brittle bones, and frequent
    fractures.

59
  • Pedigrees that could be explained by germline
    mosaicism have also been reported for several
    other well-known disorders, such as hemophilia A,
    hemophilia B, and DMD, but have only very rarely
    been seen in other dominant diseases, such as
    achondroplasia.
  • Accurate measurement of the frequency of germline
    mosaicism is difficult, but estimates suggest
    that the highest incidence is in DMD, in which up
    to 15 of the mothers of isolated cases show no
    evidence of the mutation in their somatic tissues
    and yet carry the mutation in their germline.

60
Pedigree demonstrating recurrence of the
autosomal dominant disorder osteogenesis
imperfecta. Both affected children have the same
point mutation in a collagen gene. Their father
(arrow) is unaffected and has no such mutation in
DNA from examined somatic tissues. He must have
been a mosaic for the mutation in his germline.
61
  • Geneticists and genetic counselors are aware of
    the potential inaccuracy of predicting that a
    specific autosomal dominant or X-linked phenotype
    that appears by every test to be a new mutation
    must have a negligible recurrence risk in future
    offspring.
  • Obviously, in diseases known to show germline
    mosaicism, phenotypically normal parents of a
    child whose disease is believed to be due to a
    new mutation should be informed that the
    recurrence risk is not negligible!

62
  • Furthermore, apparently non-carrier parents of a
    child with any autosomal dominant or X-linked
    disorder in which mosaicism is possible but
    unproven may have a recurrence risk that may be
    as high as 3 to 4 these couples should be
    offered whatever prenatal diagnostic tests are
    appropriate.
  • The exact recurrence risk is difficult to assess,
    however, because it depends on what proportion of
    gametes contains the mutation

63
IMPRINTING IN PEDIGREES
  • Unusual Inheritance Patterns due to Genomic
    imprinting
  • In some genetic disorders such as PWS and AS, the
    expression of the disease phenotype depends on
    whether the mutant allele has been inherited from
    the father or from the mother, a phenomenon known
    as genomic imprinting.
  • Imprinting can cause unusual inheritance patterns
    in pedigrees, as clearly demonstrated by a rare
    condition known as Albright hereditary
    osteodystrophy (AHO). AHO is characterized by
    obesity, short stature, subcutaneous
    calcifications, and brachydactyly, particularly
    of the fourth and fifth metacarpal bones.

64
A, Characteristic appearance of a patient with
Albright hereditary osteodystrophy. B, Hand
radiograph showing shortened metacarpals and
distal phalanges, especially and
characteristically the fourth metacarpal
65
  • AHO is inherited as a fully penetrant autosomal
    dominant trait. What is unusual, however, is that
    in families of individuals affected by AHO, some
    but not all of the affected patients have an
    additional clinical disorder known as
    pseudohypoparathyroidism (PHP).

66
  • In PHP, an abnormality of calcium metabolism
    typically seen with a deficiency of parathyroid
    hormone occurs but with elevated levels of
    parathyroid hormone (hence the use of the prefix
    pseudo) that is secondary to renal tubular
    resistance to the effects of parathyroid hormone.
  • PHP in an individual with the AHO phenotype is
    known as pseudohypoparathyroidism type 1a
    (PHP1a).
  • AHO with or without PHP is caused by a defect in
    the GNAS gene. GNAS is involved in transmitting
    the parathyroid hormone signal from the surface
    of renal cells to inside the cell.

67
  • A careful examination of PHP1a pedigrees shows
    that some individuals have AHO only, without the
    calcium and renal problems, whereas others have
    the physical characteristics as a component of
    PHP1a.
  • When AHO occurs without the renal tubular
    dysfunction in families in which other relatives
    have PHP1a, it is often referred to as
    pseudopseudohypoparathyroidism (PPHP).
  • Interestingly, when PPHP and PHP1a occur within
    the same family, affected brothers and sisters in
    any one sibship either all have PPHP or all have
    PHP1a what does not happen is that one sib will
    have one condition while another has the other.

68
  • This unusual pattern of inheritance can be
    explained by the fact that the defective gene
    (GNAS) in PHP1a and PPHP is imprinted only in
    certain tissues, including renal tubular cells,
    so that only the GNAS allele inherited from the
    mother is expressed in these cells while the
    father's allele is normally silent.
  • PHP1a therefore occurs only when an individual
    inherits an inactivating mutation in GNAS from
    his or her mother since the paternal copy is not
    expressed anyway, these tissues have no normal,
    functioning copy of GNAS, and resistance to the
    effects of parathyroid hormone ensues.
  • There is no imprinting, however, in most of the
    tissues of the body. In the tissues without GNAS
    imprinting, heterozygotes for one mutant GNAS
    allele all develop AHO, which is passed on as a
    simple autosomal dominant trait.

69
Pedigrees of pseudohypoparathyroidism. A, Family
with pseudohypoparathyroidism 1a (PHP1a,
solid-blue symbols) and pseudopseudohypoparathyroi
dism (PPHP, half-blue symbols), showing that all
PHP1a patients inherit the mutant GNAS gene from
their mothers, whereas all PPHP patients have a
paternally derived mutant allele.
70
  • The effect of imprinting is also seen in another
    form of AD pseudo-hypoparathyroidism, known as
    PHP type 1b.
  • PHP1b has the calcium abnormalities seen in PHP1a
    but without the physical signs of AHO.
  • PHP1b is caused by a mutation in upstream
    regulatory elements (the "imprinting center")
    that control the imprinting of the GNAS gene the
    normal function of these regulatory elements is
    to specify that the maternally inherited GNAS
    allele, and only that allele, will be expressed
    in renal tubules.

71
  • When a mutation of the imprinting control region
    is inherited from the mother, both the paternal
    allele, which is normally silent in kidney
    tubules, and the maternal allele, which is
    silenced in these tissues because of the
    deletion, fail to be expressed, and PHP1b ensues.
  • Individuals who inherit the mutation from their
    fathers, however, are asymptomatic heterozygotes
    because their maternal copy of GNAS, with its
    imprinting control region intact, is expressed
    normally in these tissues. Outside of the kidney
    and a few other tissues, both maternal and
    paternal GNAS alleles are expressed independently
    of any imprinting, and AHO therefore does not
    occur.

72
  • B, Pedigree of family with PHP1b (solid-blue
    symbols) due to a deletion in the imprinting
    control region. All affected patients inherit the
    deletion allele from their mothers heterozygotes
    with a paternal allele are unaffected.
    Heterozygotes for a deletion mutation in the
    imprinting regulatory region of the GNAS gene are
    indicated by the blue dots.

73
UNSTABLE REPEAT EXPANSIONS
  • In all of the types of inheritance presented
    earlier in this chapter, the responsible
    mutation, once it occurs, is stable from
    generation to generation.
  • In contrast, an entirely new class of genetic
    disease has been recognized, diseases due to
    unstable repeat expansions. By definition, these
    conditions are characterized by an expansion
    within the affected gene of a segment of DNA
    consisting of repeating units of three or more
    nucleotides in tandem (i.e., adjacent to each
    other).

74
  • For example, the repeat unit often consists of
    three nucleotides, such as CAG or CCG, and the
    repeat will be CAGCAGCAG CAG or CCGCCGCCG
    CCG.
  • In general, the genes associated with these
    diseases all have wild-type alleles that are
    polymorphic that is, there is a variable but
    relatively low number of repeat units in the
    normal population.

75
  • As the gene is passed from generation to
    generation, however, the number of repeats can
    increase (undergoes expansion), far beyond the
    normal polymorphic range, leading to
    abnormalities in gene expression and function.
  • The molecular mechanisms by which such expansions
    occur are not clearly understood but are likely
    to be due to a type of DNA replication error
    known as slipped mispairing.
  • The discovery of this unusual group of conditions
    has dispelled the orthodox notions of germline
    stability and provided a biological basis for
    such eccentric genetic phenomena as anticipation
    and parental transmission bias.

76
Table 7-3. Four Representative Examples of
Unstable Repeat Expansion Diseases
Repeat Number
Disease Inheritancepattern Repeat Gene Affected Location in Gene Normals intermediate Affected
Huntington disease Autosomal dominant CAG HD coding region lt36 36-39 usually affected gt40
Fragile X X-linked CGG FMR1 5' untranslated lt60 60-200 usually unaffected gt200
Myotonic dystrophy Autosomal dominant CTG DMPK 3' untranslated lt30 50-80 may be mildly affected 80-2000
Friedreich ataxia Autosomal recessive AAG FRDA intron lt34 36-100 gt100
May have tremor-ataxia syndrome or premature
ovarian failure.
77
  • More than a dozen diseases are known to result
    from unstable repeat expansions. All of these
    conditions are primarily neurological.
  • A dominant inheritance pattern occurs in some,
    X-linked in others, and recessive inheritance in
    still others. The degree of expansion of the
    repeat unit that causes disease is sometimes
    subtle (as in the rare disorder oculopharyngeal
    muscular dystrophy) and sometimes explosive (as
    in congenital myotonic dystrophy or severe
    fragile X syndrome).

78
  • Other differences between the various unstable
    repeat expansion diseases include
  • the length and base sequence of the repeated
    unit
  • the number of repeated units in normal,
    presymptomatic and fully affected individuals
  • the location of the repeated unit within genes
  • the pathogenesis of the disease
  • the degree to which the repeated units are
    unstable during meiosis or mitosis and
  • parental bias in when expansion occurs.

79
Polyglutamine Disorders
  • Huntington Disease
  • Huntington disease (HD) is a well-known disorder
    that illustrates many of the common genetic
    features of the polyglutamine disorders caused by
    expansion of an unstable repeat.
  • HD was first described by the physician George
    Huntington in 1872 in an American kindred of
    English descent. The neuropathology is dominated
    by degeneration of the striatum and the cortex.
  • Patients first present clinically in midlife and
    manifest a characteristic phenotype of motor
    abnormalities (chorea, dystonia), personality
    changes, a gradual loss of cognition, and
    ultimately death.

80
  • For a long time, HD was thought to be a typical,
    AD. Although homozygotes may have a more rapid
    course of their disease.
  • There are, however, obvious peculiarities in its
    inheritance that could not be explained by simple
    AD inheritance.
  • First, the age at onset of HD is variable only
    about half the individuals who carry a mutant HD
    allele show symptoms by the age of 40 years.
  • Second, the disease appears to develop at an
    earlier and earlier age when it is transmitted
    through the pedigree, a phenomenon referred to as
    anticipation, but only when it is transmitted by
    an affected father and not by an affected mother.

81
  • These are now readily explained by the discovery
    that the mutation is composed of an abnormally
    long expansion of a stretch of the nucleotides
    CAG, the codon specifying glutamine, in the
    coding region of a gene for a protein of unknown
    function called huntingtin.
  • Normal individuals carry between 9 and 35 CAG
    repeats in their HD gene, with the average being
    18 or 19.
  • Individuals affected with HD have 40 or more
    repeats, with the average being around 46. A
    borderline repeat number of 36 to 39, although
    usually associated with HD, can be found in a few
    individuals who show no signs of the disease even
    at a fairly advanced age.
  • Once an expansion increases to greater than 39,
    however, disease always occurs, and the larger
    the expansion, the earlier the onset of the
    disease.

82
Figure 7-27 Graph correlating approximate age at
onset of Huntington disease with the number of
CAG repeats found in the HD gene. The solid line
is the average age at onset, and the shaded area
shows the range of age at onset for any given
number of repeats
83
Figure 7-28 Pedigree of family with Huntington
disease. Shown beneath the pedigree is a Southern
blot analysis for CAG repeat expansions in the
huntingtin gene. In addition to a normal allele
containing 25 CAG repeats, individual I-1 and his
children II-1, II-2, II-4, and II-5 are all
heterozygous for expanded alleles, each
containing a different number of CAG repeats.
I-1, who developed HD at the age of 64 years and
is now deceased, had an abnormal repeat length of
37. He has three affected children, two of whom
have repeat lengths of 55 and 70 and developed
disease in their 40s, and a son with juvenile HD
and 103 CAG repeats in his huntingtin gene.
Individual II-1 is unaffected at the age of 50
years but will develop the disease later in life.
Individuals I-2 and II-3 have two alleles of
normal length (25). Repeat lengths were confirmed
by PCR analysis.
84
  • How, then, does an individual come to have an
    expanded CAG repeat in his or her HD gene?
  • Most commonly, he or she inherits it as a
    straightforward autosomal dominant trait from an
    affected parent who already has an expanded
    repeat (gt36).
  • In contrast to stable mutations, however, the
    size of the repeat may expand on transmission,
    resulting in earlier onset disease in later
    generations on the other hand, repeat numbers in
    the range of 40 to 50 may not result in disease
    until later in life, thereby explaining the
    age-dependent penetrance.

85
  • In this pedigree, individual I-1, now deceased,
    was diagnosed with HD at the age of 64 years and
    had an expansion of 37 CAG repeats.
  • Four of his children inherited the expanded
    allele, and in all four of them, the expansion
    increased over that found in individual I-1
  • Individual II-5, in particular, has the largest
    number of repeats and became symptomatic during
    adolescence. Individual II-1, in contrast,
    inherited an expanded allele but remains
    asymptomatic and will likely develop the disease
    sometime later in life.

86
  • On occasion, unaffected individuals carry alleles
    with repeat lengths at the upper limit of the
    normal range (29 to 35 CAG repeats) that,
    however, can expand during meiosis to 40 or more
    repeats.
  • CAG repeat alleles at the upper limits of normal
    that do not cause disease but are capable of
    expanding into the disease-causing range are
    known as premutations.
  • Expansion in HD shows a paternal transmission
    bias and occurs most frequently during male
    gametogenesis, which is why the severe
    early-onset juvenile form of the disease, seen
    with the largest expansions (70 to 121 repeats),
    is always paternally inherited.

87
  • Expanded repeats may continue to be unstable
    during mitosis in somatic cells, resulting in
    some degree of somatic mosaicism for the number
    of repeats in different tissues from the same
    patient.
  • The largest known group of HD patients lives in
    the region of Lake Maracaibo, Venezuela these
    patients are descendants of a single individual
    who introduced the gene into the population early
    in the 19th century.
  • About 100 living affected persons and another
    900, each at 50 risk, are currently known in the
    Lake Maracaibo community.
  • High frequency of a disease in a local population
    descended from a small number of individuals, one
    of whom carried the gene responsible for the
    disease, is an example of founder effect.

88
Spinobulbar Muscular Atrophy and Other
Polyglutamine Disorders
  • In addition to HD, other neurological diseases
    are caused by CAG expansions encoding
    polyglutamine, such as X-linked recessive
    spinobulbar muscular atrophy and the various
    autosomal dominant spinocerebellar ataxias.
  • These conditions differ in the gene involved, the
    normal range of the repeat, the threshold for
    clinical disease caused by expansion, and the
    regions of the brain affected.
  • They all share with HD the fundamental
    characteristic that results from instability of a
    stretch of repeated CAG nucleotides leading to
    expansion of a glutamine tract in a protein.

89
Fragile X Syndrome
  • The fragile X syndrome is the most common
    heritable form of moderate MR and is second only
    to Down syndrome among all causes of MR in males.
  • The name refers to a cytogenetic marker on the X
    chromosome at Xq27.3, a "fragile site" in which
    the chromatin fails to condense properly during
    mitosis.
  • The syndrome is inherited as an X-linked disorder
    with penetrance in females in the 50 to 60
    range.
  • The fragile X syndrome has a frequency of at
    least 1 in 4000 male births and is so common that
    it requires consideration in the differential
    diagnosis of MR in both males and females.
  • Testing for the fragile X syndrome is among the
    most frequent indications for DNA analysis,
    genetic counseling, and prenatal diagnosis.

90
Figure 7-30 The fragile site at Xq27.3 associated
with X-linked mental retardation
91
  • The disorder is caused by another unstable repeat
    expansion, a massive expansion of another triplet
    repeat, CGG, located in the 5' untranslated
    region of the first exon of a gene called FMR1
    (fragile X mental retardation 1).
  • The normal number of repeats is up to 60, whereas
    as many as several thousand repeats are found in
    patients with the "full" fragile X syndrome
    mutation.
  • More than 200 copies of the repeat lead to
    excessive methylation of cytosines in the
    promoter of FMR1 this interferes with
    replication or chromatin condensation or both,
    producing the characteristic chromosomal fragile
    site, a form of DNA modification that prevents
    normal promoter function or blocks translation.

92
  • Triplet repeat numbers between 60 and 200
    constitute a special intermediate premutation
    stage of the fragile X syndrome.
  • Expansions in this range are unstable when they
    are transmitted from mother to child and have an
    increasing tendency to undergo full expansion to
    more than 200 copies of the repeat during
    gametogenesis in the female (but almost never in
    the male), with the risk of expansion increasing
    dramatically with increasing premutation size.
  • Carriers of premutations can develop an
    adult-onset neurological disorder of cerebellar
    dysfunction and neurological deterioration, known
    as the fragile X-associated tremor/ataxia
    syndrome.
  • In addition, approximately one quarter of female
    carriers of premutations will experience
    premature ovarian failure by the age of 40 years.

93
Figure 7-29 Characteristic facial appearance of a
patient with the fragile X syndrome
94
Figure 7-31 Frequency of expansion of a
premutation triplet repeat in FMR1 to a full
mutation in oogenesis as a function of the length
of the premutation allele carried by a
heterozygous female. The risk of fragile X
syndrome to her sons is approximately half this
frequency, since there is a 50 chance a son will
inherit the expanded allele. The risk of fragile
X syndrome to her daughters is approximately
one-fourth this frequency, since there is a 50
chance a daughter would inherit the full
mutation, and penetrance of the full mutation in
a female is approximately 50
95
Myotonic Dystrophy
  • Myotonic dystrophy (dystrophia myotonica, or DM)
    is inherited as an autosomal dominant myopathy
    characterized by myotonia, muscular dystrophy,
    cataracts, hypogonadism, diabetes, frontal
    balding, and changes in the electroencephalogram.
  • The disease is notorious for lack of penetrance,
    pleiotropy, and its variable expression in both
    clinical severity and age at onset.
  • The DM congenital form, is particularly severe
    and may be life-threatening as well as a cause of
    MR.
  • Virtually every child with the congenital form is
    the offspring of an affected mother, who herself
    may have only a mild expression of the disease
    and may not even know that she is affected. Thus,
    pedigrees of DM, like those of HD and fragile X
    syndrome, show clear evidence of anticipation.

96
  • DM is also associated with amplification of a
    triplet repeat, in this case a CTG triplet
    located in the 3' untranslated region of a
    protein kinase gene (DMPK).
  • The normal range for repeats in DMPK is 5 to 30
    carriers of repeats in the range of 38 to 54
    (premutations) are usually asymptomatic but have
    an increased risk of passing on fully expanded
    repeats.
  • Mildly affected individuals have about 50 to 80
    copies the severity increases and age at onset
    decreases the longer the expansion.

97
Myotonic dystrophy, an autosomal dominant
condition with variable expression in clinical
severity and age at onset. The grandmother in
this family (left) had bilateral cataracts but
has no facial weakness or muscle symptoms her
daughter was thought to be unaffected until after
the birth of her severely affected child, but she
now has moderate facial weakness and ptosis, with
myotonia, and has had cataract extraction. The
child has congenital myotonic dystrophy
98
  • Severely affected individuals can have more than
    2000 copies. Either parent can transmit an
    amplified copy, but males can pass on up to 1000
    copies of repeat, whereas really massive
    expansions containing many thousands of repeats
    occur only in female gametogenesis. Because
    congenital DM is due to huge expansions in the
    many thousands, this form of myotonic dystrophy
    is therefore almost always inherited from an
    affected mother.

99
Friedreich Ataxia
  • Friedreich ataxia (FRDA), a spinocerebellar
    ataxia, constitutes a fourth category of triplet
    repeat disease.
  • The disease is inherited in an AR pattern, in
    contrast to HD, DM, and fragile X syndrome. The
    disorder is usually manifested before adolescence
    and is generally characterized by incoordination
    of limb movements, difficulty with speech,
    diminished or absent tendon reflexes, impairment
    of position and vibratory senses, cardiomyopathy,
    scoliosis, and foot deformities.
  • In most cases, Friedreich ataxia is caused by
    amplification of still another triplet repeat,
    AAG, located this time in an intron of a gene
    that encodes a mitochondrial protein called
    frataxin, which is involved in iron metabolism.

100
  • In normal individuals, the repeat length varies
    from 7 to 34 copies, whereas repeat expansions in
    the patients are typically between 100 and 1200
    copies.
  • Expansion within the intron interferes with
    normal expression of the frataxin gene because
    Friedreich ataxia is recessive, loss of
    expression from both alleles is required to
    produce the disease.
  • In fact, 1 to 2 of FRDA patients are known to
    be compound heterozygotes in whom one allele is
    the common amplified intronic AAG repeat mutation
    and the other a nucleotide mutation

101
Similarities and Differences Among Unstable
Repeat Expansion Disorders
  • A comparison of HD (and the other polyglutamine
    neurodegeneration diseases) with the fragile X
    syndrome, DM, and FRDA reveals some similarities
    but also many differences
  • Although unstable repeat expansions of a
    trinucleotide are involved in all four types of
    disease, the expansion in the polyglutamine
    diseases is in the coding region and ranges from
    40 to 120 copies of the CAG, whereas the repeat
    expansions in fragile X syndrome, DM, and FRDA
    involve different triplet nucleotides, contain
    hundreds to thousands of repeated triplets, and
    are located in untranslated portions of the FMR1,
    DMPK, and FRDA genes, respectively.

102
  • Premutation expansions causing an increased risk
    for passing on full mutations are the rule in all
    four of these disorders, and anticipation is
    commonly seen in pedigrees of the dominant and
    X-linked diseases (HD, fragile X syndrome, and
    DM).
  • However, the number of repeats in premutation
    alleles in HD is 29 to 35, similar to what is
    seen in DM but far less than in fragile X
    syndrome.

103
  • Premutation carriers can develop significant
    disease in fragile X syndrome but are, by
    definition, disease-free in HD and DM. The
    expansion of premutation alleles occurs in the
    female primarily in FRDA, DM, and fragile X
    syndrome the largest expansions causing juvenile
    onset HD occur in the male germline.
  • Finally, the degree of mitotic instability in
    fragile X syndrome, DM, and FRDA is far greater
    than that seen in HD and results in much greater
    variability in the numbers of repeats found among
    cells of the same tissue and between different
    somatic tissues in a single individual.

104
CONDITIONS THAT MAY MIMIC MENDELIAN INHERITANCE
OF SINGLE-GENE DISORDERS
  • A pedigree pattern sometimes simulates a
    single-gene pattern even though the disorder does
    not have a single-gene basis.
  • It is easy to be misled in this way by
    teratogenic effects by certain types of
    inherited chromosome disorders, such as balanced
    translocations or by environmental exposures
    shared among family members.

105
  • Inherited single-gene disorders can usually be
    distinguished from these other types of familial
    disorders by their typical mendelian segregation
    ratios within kindreds.
  • Confirmation that a familial disease is due to
    mutations in a single gene eventually requires
    demonstration of defects at the level of the gene
    product, or the gene itself.

106
  • There is also a class of disorders called
    segmental aneusomies, in which there is a
    deficiency or excess of two or more genes at
    neighboring loci on a chromosome, due to a
    deletion or a duplication or triplication of an
    entire segment of DNA.
  • Here the phenotype, referred to as a contiguous
    gene syndrome, results from alterations in the
    copy number of more than one gene and yet shows
    typical mendelian segregation ratios, with a
    usually dominant inheritance pattern, because the
    segmental aneusomy is passed on as if it were a
    single mutant allele.

107
  • Examples include
  • autosomal dominant Parkinson disease due to a
    triplication of an approximately 2-Mb region of
    chromosome 4q
  • autosomal dominant velocardiofacial syndrome,
    where the phenotype is caused by deletions of
    millions of base pairs of DNA encoding multiple
    genes at 22q11.2 and
  • the X-linked syndrome of choroideremia (a retinal
    degeneration), deafness, and mental retardation,
    caused by a deletion of at least three loci in
    band Xq21

108
MATERNAL INHERITANCE OF DISORDERS CAUSED BY
MUTATIONS IN THE MITOCHONDRIAL GENOME
  • Some pedigrees of inherited diseases that could
    not be explained by typical mendelian inheritance
    of nuclear genes are now known to be caused by
    mutations of the mitochondrial genome and to
    manifest maternal inheritance.
  • Disorders caused by mutations in mitochondrial
    DNA demonstrate a number of unusual features that
    result from the unique characteristics of
    mitochondrial biology and function.

109
The Mitochondrial Genome
  • The mt genome consists of a circular chr., 16.5
    kb.
  • Most cells contain at least 1000 mtDNA molecules,
    distributed among hundreds of individual mt.
  • A remarkable exception is the mature oocyte,
    which has more than 100,000 copies of mtDNA,
    composing about one third of the total DNA
    content of these cells.
  • Mitochondrial DNA (mtDNA) contains 37 genes. The
    genes encode 13 polypeptides that are subunits of
    enzymes of oxidative phosphorylation, two types
    of rRNA, and 22 tRNAs required for translating
    the transcripts of the mitochondria-encoded
    polypeptides.

110
  • More than 100 different rearrangements and 100
    different point mutations have been identified in
    mtDNA that can cause human disease, often
    involving the central nervous and musculoskeletal
    systems (e.g., myoclonic epilepsy with ragged-red
    fibers).
  • The diseases that result from these mutations
    show a distinctive pattern of inheritance because
    of three unusual features of mitochondria
    replicative segregation, homoplasmy and
    heteroplasmy, and maternal inheritance.

111
Replicative Segregation
  • The first unique feature of the mt. chromosome is
    the absence of the tightly controlled segregation
    seen during mitosis and meiosis of the 46 nuclear
    chromosomes.
  • At cell division, the multiple copies of mtDNA in
    each of the mitochondria in a cell replicate and
    sort randomly among newly synthesized
    mitochondria.
  • The mitochondria, in turn, are distributed
    randomly between the two daughter cells. This
    process is known as replicative segregation.

112
Homoplasmy-Heteroplasmy
  • The second feature arises from the fact that most
    cells contain many copies of mtDNA molecules.
  • When a mutation arises in the mtDNA, it is at
    first present in only one of the mtDNA molecules
    in a mitochondrion. With replicative segregation,
    however, a mitochondrion containing a mutant
    mtDNA will acquire multiple copies of the mutant
    molecule. With cell division, a cell containing a
    mixture of normal and mutant mtDNAs can
    distribute very different proportions of mutant
    and wild-type mitochondrial DNA to its daughter
    cells.

113
  • One daughter cell may, by chance, receive
    mitochondria that contain only a pure population
    of normal mtDNA or a pure population of mutant
    mtDNA (a situation known as homoplasmy).
  • Alternatively, the daughter cell may receive a
    mixture of mitochondria, some with and some
    without mutation (heteroplasmy).
  • Because the phenotypic expression of a mutation
    in mtDNA depends on the relative proportions of
    normal and mutant mtDNA in the cells making up
    different tissues, reduced penetrance, variable
    expression, and pleiotropy are all typical
    features of mitochondrial disorders.

114
Homoplasmy and Heteroplasmy
  • Figure 7-33 Replicative segregation of a
    heteroplasmic mitochondrial mutation. Random
    partitioning of mutant and wild-type mitochondria
    through multiple rounds of mitosis produces a
    collection of daughter cells with wide variation
    in the proportion of mutant and wild-type
    mitochondria carried by each cell. Cell and
    tissue dysfunction results when the fraction of
    mitochondria that are carrying a mutation exceeds
    a threshold level. N, nucleus.

115
Maternal Inheritance of mtDNA
  • The final mtDNA is its maternal inheritance.
    Sperm mitochondria are generally eliminated from
    the embryo, so that mtDNA is inherited from the
    mother. Thus, all the children of a female who is
    homoplasmic for a mtDNA mutation will inherit the
    mutation, whereas none of the offspring of a male
    carrying the same mutation will inherit the
    defective DNA.
  • Maternal inheritance in the presence of
    heteroplasmy in the mother is associated with
    additional features of mtDNA genetics that are of
    medical significance. First, the number of mtDNA
    molecules within developing oocytes is reduced
    before being subsequently amplified to the huge
    total seen in mature oocytes. This restriction
    and subsequent amplification of mtDNA during
    oogenesis is termed the mitochondrial genetic
    bottleneck.

116
  • Consequently, the variability in the percentage
    of mutant mtDNA molecules seen in the offspring
    of a mother with heteroplasmy for a mtDNA
    mutation arises, at least in part, from the
    sampling of only a subset of the mtDNAs during
    oogenesis.
  • As might be expected, mothers with a high
    proportion of mutant mtDNA molecules are more
    likely to produce eggs with a higher proportion
    of mutant mtDNA and therefore are more likely to
    have clinically affected offspring than are
    mothers with a lower proportion.
  • One exception to maternal inheritance occurs when
    the mother is heteroplasmic for deletion mutation
    in her mtDNA for unknown reasons, deleted mtDNA
    molecules are generally not transmitted from
    clinically affected mothers to their children.

117
  • Figure 7-34 Pedigree of Leber hereditary optic
    neuropathy, a form of spontaneous blindness
    caused by a defect in mitochondrial DNA.
    Inheritance is only through the maternal lineage,
    in agreement with the known maternal inheritance
    of mitochondrial DNA. No affected male transmits
    the disease.

118
  • Although mitochondria are almost always inherited
About PowerShow.com