Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

• DOI: 10.1073/pnas.0600158103
• Publication Date: 2006-04-11T00:44:14Z
• Authors: Annie P. Chiang; John S. Beck; Hsan-Jan Yen; Marwan K. Tayeh; Todd E. Scheetz; Ruth E. Swiderski; Darryl Y. Nishimura; Terry A. Braun; Kwang-Youn A. Kim; Jian Huang; Khalil Elbedour; Rivka Carmi; Diane C. Slusarski; Thomas L. Casavant; Edwin M. Stone; Val C. Sheffield
• Keywords: 0303 health sciences; Genome, Human; Ubiquitin-Protein Ligases; DNA Mutational Analysis; Homozygote; Chromosome Mapping; Zebrafish Proteins; Polymorphism, Single Nucleotide; 3. Good health; Tripartite Motif Proteins; 03 medical and health sciences; Mutation; Animals; Humans; Bardet-Biedl Syndrome; Zebrafish; Oligonucleotide Array Sequence Analysis; Transcription Factors

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 theTRIM32gene, 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 thatTRIM32is 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.