Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3)

Annie P Chiang; Darryl Nishimura; Charles Searby; Khalil Elbedour; Rivka Carmi; Amanda L Ferguson; Jenifer Secrist; Terry Braun; Thomas Casavant; Edwin M Stone; Val C Sheffield

doi:10.1086/423903

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Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3)

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Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3)

Annie P Chiang, Darryl Nishimura, Charles Searby, Khalil Elbedour, Rivka Carmi, Amanda L Ferguson, Jenifer Secrist, Terry Braun, Thomas Casavant, Edwin M Stone, …

American journal of human genetics, Vol.75(3), pp.475-484

09/2004

DOI: 10.1086/423903

PMCID: PMC1182025

PMID: 15258860

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Abstract

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Eight BBS loci have been mapped, and seven genes have been identified. BBS3 was previously mapped to chromosome 3 by linkage analysis in a large Israeli Bedouin kindred. The rarity of other families mapping to the BBS3 locus has made it difficult to narrow the disease interval sufficiently to identify the gene by positional cloning. We hypothesized that the genomes of model organisms that contained the orthologues to known BBS genes would also likely contain a BBS3 orthologue. Therefore, comparative genomic analysis was performed to prioritize BBS candidate genes for mutation screening. Known BBS proteins were compared with the translated genomes of model organisms to identify a subset of organisms in which these proteins were conserved. By including multiple organisms that have relatively small genome sizes in the analysis, the number of candidate genes was reduced, and a few genes mapping to the BBS3 interval emerged as the best candidates for this disorder. One of these genes, ADP-ribosylation factor-like 6 (ARL6), contains a homozygous stop mutation that segregates completely with the disease in the Bedouin kindred originally used to map the BBS3 locus, identifying this gene as the BBS3 gene. These data illustrate the power of comparative genomic analysis for the study of human disease and identifies a novel BBS gene.

Genes, Plant

Humans

Molecular Sequence Data

Codon

Chromosomes, Human, Pair 3 - ultrastructure

DNA Mutational Analysis

Cloning, Molecular

Bardet-Biedl Syndrome - genetics

Genes, Fungal

ADP-Ribosylation Factors - genetics

Amino Acid Sequence

Computational Biology

Genotype

Chromosome Mapping

Sequence Analysis, DNA

Syndrome

Databases as Topic

Sequence Homology, Amino Acid

Homozygote

Animals

Alleles

Models, Genetic

Israel

Mutation

Codon, Terminator

Genome

Genome, Human

Details

Title: Subtitle: Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3)
Creators: Annie P Chiang - Department of Computer and Electrical Engineering, University of Iowa, Iowa City, IA 52242, USA
Darryl Nishimura
Charles Searby
Khalil Elbedour
Rivka Carmi
Amanda L Ferguson
Jenifer Secrist
Terry Braun
Thomas Casavant
Edwin M Stone
Val C Sheffield
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.75(3), pp.475-484
DOI: 10.1086/423903
PMID: 15258860
PMCID: PMC1182025
NLM abbreviation: Am J Hum Genet
ISSN: 0002-9297
eISSN: 1537-6605
Publisher: United States
Grant note: R01 EY011298 / NEI NIH HHS P50-HL-55006 / NHLBI NIH HHS P50 HL055006 / NHLBI NIH HHS R01-EY-11298 / NEI NIH HHS
Language: English
Date published: 09/2004
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9983979957502771

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