Patterns of Single-Gene Inheritance

About This Presentation

Title:

Patterns of Single-Gene Inheritance

Description:

... the codon specifying glutamine, in the coding region of a gene for a protein of unknown function called ... leading to premature coronary heart disease. – PowerPoint PPT presentation

Number of Views:182

Avg rating:3.0/5.0

Slides: 123

Provided by: Fad45

Category:

more less

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.

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.

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 affected1/2 unaffected
Affected by affected D/d D/d 1/4 D/D, 1/2 D/d, 1/4 d/d If strictly dominant3/4 affected1/4 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.

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.

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.

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.

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.

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.

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.

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

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).

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

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

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.

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.

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.

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.

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.

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.

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.

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!

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).

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.

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.

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.

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.

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).

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

Patterns of Single-Gene Inheritance - PowerPoint PPT Presentation

Patterns of Single-Gene Inheritance

... the codon specifying glutamine, in the coding region of a gene for a protein of unknown function called ... leading to premature coronary heart disease. – PowerPoint PPT presentation