Cause: A rare inherited disease

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Gaucher Disease
Phillipe Charles Ernest Gaucher

• Cause A rare inherited disease
• (genetic disorder), caused by enzyme
  deficiency
• (glucocerebrosidase GBA), which results in
  
• accumulation of the lipid glucocerebrosides
• in cells lysosomes.
• Highest prevalence in Ashkenazi Jewish
  population.

1882

• Traditional therapy total or partial
• removal of the spleen, blood transfusions,
• orthopedic procedures and bone marrow
• transplantation.
• Enzyme replacement therapy, very costly
• 100,000 - 400,000 US/patient/year.

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Gaucher Disease
Characterization remarkable degree of
variability in clinical signs and
symptoms. Clinical signs anemia, bone damage,
enlarged liver and spleen (most patients have
Type 1 disease), some develop additional severe
central nervous system damage (Type 2 3,
neuronopathic). Type 1 is the most common
genetic disease affecting Ashkenazi Jews. As
many as 1 in 10 Ashkenazi Jews and 1 in 100
people in the general population may be
carrying the gene mutation that causes Type 1
Gauchers.
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What is OMIM ? Online Mendelian Inheritance
in Man. A catalog of human genes and genetic
disorders.
Using OMIM

• Start with a syndrome search or a gene using
  OMIM.
• Identify the gene for the syndrome (if not
  known).
• Locate the gene on the genome ( other genes
  nearby).
• Information about the gene in LocusLink.
• Links to sequences and structure information.
• View structurally similar proteins.

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http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbO
MIM
http//bioinformatics.weizmann.ac.il/cards/
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OMIM search - Gaucher
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http//bioinformatics.weizmann.ac.il/cards/
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NCBI
ENTREZ - PubMed
http//www.ncbi.nlm.nih.gov/
http//www.ncbi.nlm.nih.gov/Sitemap/index.html
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NCBI-ENTREZ

• A Web-based retrieval system
• developed by NCBI at the NLM,
• part of NCBI's Entrez.
• PubMed is a database of bibliographic
  information drawn
• primarily from the life sciences literature.
• Links to full-text articles as well as links
  to other sites
• such as libraries and sequencing centers.
• PubMed provides access and links to the
  integrated molecular
• biology databases maintained by NCBI.

The diagram illustrates the relationships between
the primary information resources in Entrez.
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• The largest, most used and best known of NLM
  databases (90 of all bio-medical searches done),
  available free on the internet.
• Citations From 4,300 worldwide journals
  currently in
• 30 languages.
• Weekly update 8,000 completed references are
  added each Saturday (gt 400,000 added per year).
• Time coverage 1966-present (a few references
  from
• the late 1800?s).
• Content gt 40 databases online.
• Database size gt 20 x 106 records.
• End result gt 9 million searches per month.

http//www.nlm.nih.gov/bsd/pubmed_tutorial/m1001.h
tml
http//www.nlm.nih.gov/medlineplus/
http//www4.ncbi.nlm.nih.gov/PubMed/
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http//www.nlm.nih.gov/mesh/meshhome.html
http//www.ncbi.nlm.nih.gov/PubMed/meshbrowserhelp
.html
MeSH is a vocabulary of medical and scientific
terms assigned to most documents in PubMed by a
team of experts. It is most useful in starting a
search.
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(No Transcript)
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Searching the Literature

• PubMed Indexing
• MESH (Medical Subject Heading)
• Use a term to limit retrieval Human, animal,
  male, female, age group,
• organism, etc..
• Publication Type
• Review, clinical trial, letter, journal article,
  etc.
• Search Terms By
• Author name, title word, text word, journal
  title,
• publication date, phrase, or any combination of
  these.
• NOTE Words are automatically added, but
  Boolean operators
• (AND, OR, NOT, in UPPER CASE) are welcome.
• Guide to Using PubMed http//www.lib.ucdavis.edu/
  healthsci/usingpubmedfull.html

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Searching the Literature
Entrez - Boolean operators

• AND, OR, NOT
• Bacteria AND virus NOT phage
• (bacteria AND virus) NOT phage
• HIV-1 OR bacterial protease
• hiv OR (bacterial AND protease)

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Searching the Literature
http//www.ncbi.nlm.nih.gov/RefSeq/key.html
Entrez - Using limits
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Start query using NUCLEOTIDE and GENES NAME
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A Simple GenBank Record from ENTREZ
II
I
citation
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Keyword, Source-Organism (I)
Accepted common name
Keywords. SOURCE human. ORGANISM
Homo sapiens Eukaryota Metazoa Chordata
Craniata Vertebrata Euteleostomi
Mammalia Eutheria Primates Catarrhini
Hominidae Homo
Scientific name
Taxonomic lineage according to GenBank
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Sequences and Databases (II) locus, accession
, gi, acc. version
GB Division
Sequence Length
Modification Date
Locus Name
Mol. Type
LOCUS NM_000157 2275 bp mRNA PRI
27-AUG-2001
DEFINITION Homo Sapiens glucosidase, beta acid
(includes glucosylceramidase) (GBA), ,mRNA
The number a sequence gets when
published, unique to entry. does not change when
record is updated.
Accession Num.
ACCESSION NM_000157
VERSION NM_000157.1 GI 4503934
gi? Num.
Gene info identifier The number a sequence
gets when entering database (GB).
Accession Version
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Feature Table
FEATURES Location/Qualifiers source
1..2275 /organism"Homo sapiens" /db_xref"
taxon9606" /chromosome"1" /map?"1q21"? gene
1..2275 /gene"GBA" /note"GLUC" /db_xref"
LocusID2629" /db_xref"MIM230800"

• Additional information
• References
• Variations

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Feature Table - cont.
atgcgtcgctatgataaccgggc..gtagagtcagagtcggatag
CDS 123..1733 (protein coding sequence,
including stop) /gene"GBA" /ECnumber"3.2.1.45" /
note"Glucosidase, beta acid" /codonstart1 /db_x
ref"LocusID2629" /db_xref"MIM230800" /product
"glucosidase, beta acid (includes
glucosylceramidase)" /protein_id"NP
000148.1" /db_xref"GI4503935" /translation"MEFS
SPSREECPKPLSRVSIMAGSLTGLLLLQAVSWASGARPCI PKSFGYSSV
VCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANHTGT
GLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEG
IGYNIIRV PMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIH
RALQLAQRPVSLLASPW TSPTWLKTNGAVNGKGSLKGQPGDIYHQTWAR
YFVKFLDAYAEHKLQFWAVTAENEPS AGLLSGYPFQCLGFTPEHQRDFI
ARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVV LTDPEAAKYVHGIA
VHWYLDFLAPAKATLGETHRLFPNTMLFASEACVGSKFWEQSVR LGSWD
RGMQYSHSIITNLLYHVVGWTDWNLALNPEGGPNWVRNFVDSPIIVDITK
DTF YKQPMFYHLGHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAV
VVVLNRSSKDVP LTIKDPAVGFLETISPGYSIHTYLWHRQ"
Reading frame
Protein id
Protein sequence
nucleotide sequence
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Start query using PROTEIN and GENES NAME
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• Amino acids Nucleotide sequences.

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FASTA format
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Common Database Identifiers

• Locus name - original identifier of GenBank
  record.
• Originally - first 3 letters of organism followed
  by code for gene
• (example HUMBB for human beta-globin).
• Problems unmaintainable due to growth of data.
• Homologous genes not named the
  same.
• Accession number - has no biological meaning.
• Originally - Uppercase letter followed by 5
  digits (example U00002).
• Currently - 2 uppercase letters followed by 6
  digits (example BC037153).
• Versions BC03715.1
• GenInfo number - identifier for a particular
  sequence only.
• Each entry gets a unique gi number (example GI
  22477487).
• Not subject to versioning - entry always remains
  the same.
• PubMed number.

http//www.ncbi.nlm.nih.gov/Sitemap/samplerecord.h
tmlLocusA
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Related records in PubMed, OMIM, RefSeq,
GenBank nucleotide, Protein, HomoloGene,
UniGene, Variation data (dbSNP).
http//www.ncbi.nlm.nih.gov/LocusLink/list.cgi
http//www.ncbi.nlm.nih.gov/LocusLink/help.htmlqu
ery
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Identify Known Mutations (SNP link)
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Identify Known Mutations (Allelic Variants
section)
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Information Obtained So-Far About Gaucher Disease

• Cause Glucocerebrosidase deficiency
• (parallel names of the defective enzyme).
• Clinical signs.
• Frequency High in Ashkenazi Jewish population.
• Diagnosis Between one week of life and 86
  years.
• Autosomal recessive disorder.
• Classification 3 Types (I -non-cerebral, II,
  III -cerebral).
• Gene map locus 1q21.
• Presence of pseudo-gene.
• Another gene involved Prosaposin - found in
  locus 10q22.1.

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• Other Biological Text Based
• Searches
• SRS (sequence retrieval system)
• at EBI, England.
• http//srs.ebi.ac.uk/
• STAG at DDBJ, Japan.
• http//stag.genome.ad.jp/
• Expasy at SIB
• (Swiss Institute of
• Bio informatics),
• Switzerland.
• http//www.expasy.org/

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SRS Sequence Retrival Systemhttp//srs.ebi.ac.uk
/
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Deambulum
http//www.infobiogen.fr/services/deambulum/englis
h/