title: Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).
abstract: The identification of mutations in genes that cause human diseases has largely been accomplished through the use of positional cloning, which relies on linkage mapping. In studies of rare diseases, the resolution of linkage mapping is limited by the number of available meioses and informative marker density. One recent advance is the development of high-density SNP microarrays for genotyping. The SNP arrays overcome low marker informativity by using a large number of markers to achieve greater coverage at finer resolution. We used SNP microarray genotyping for homozygosity mapping in a small consanguineous Israeli Bedouin family with autosomal recessive Bardet-Biedl syndrome (BBS; obesity, pigmentary retinopathy, polydactyly, hypogonadism, renal and cardiac abnormalities, and cognitive impairment) in which previous linkage studies using short tandem repeat polymorphisms failed to identify a disease locus. SNP genotyping revealed a homozygous candidate region. Mutation analysis in the region of homozygosity identified a conserved homozygous missense mutation in the TRIM32 gene, a gene coding for an E3 ubiquitin ligase. Functional analysis of this gene in zebrafish and expression correlation analyses among other BBS genes in an expression quantitative trait loci data set demonstrate that TRIM32 is a BBS gene. This study shows the value of high-density SNP genotyping for homozygosity mapping and the use of expression correlation data for evaluation of candidate genes and identifies the proteasome degradation pathway as a pathway involved in BBS.
authors.affiliation: Department of Electrical Engineering, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Annie P
authors.initials: AP
authors.lastname: Chiang
authors.forename: John S
authors.initials: JS
authors.lastname: Beck
authors.forename: Hsan-Jan
authors.initials: HJ
authors.lastname: Yen
authors.forename: Marwan K
authors.initials: MK
authors.lastname: Tayeh
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Swiderski
authors.forename: Darryl Y
authors.initials: DY
authors.lastname: Nishimura
authors.forename: Terry A
authors.initials: TA
authors.lastname: Braun
authors.forename: Kwang-Youn A
authors.initials: KY
authors.lastname: Kim
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Khalil
authors.initials: K
authors.lastname: Elbedour
authors.forename: Rivka
authors.initials: R
authors.lastname: Carmi
authors.forename: Diane C
authors.initials: DC
authors.lastname: Slusarski
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Casavant
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D015894:Genome, Human; D006720:Homozygote; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D029961:Zebrafish Proteins; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases