Exome capture sequencing identifies a novel mutation in BBS4.

TitleExome capture sequencing identifies a novel mutation in BBS4.
Publication TypeJournal Article
Year of Publication2011
AuthorsWang, H, Chen, X, Dudinsky, L, Patenia, C, Chen, Y, Li, Y, Wei, Y, Abboud, EB, Al-Rajhi, AA, Lewis, RAlan, Lupski, JR, Mardon, G, Gibbs, RA, Perkins, BD, Chen, R
JournalMol Vis
Date Published2011
KeywordsAlleles, Animals, Base Sequence, Chromosome Mapping, Consanguinity, Exome, Exons, Female, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Leber Congenital Amaurosis, Male, Microtubule-Associated Proteins, Molecular Sequence Data, Mutation, Missense, Pedigree, Polymorphism, Single Nucleotide, Proteins, Retina, Rhodopsin, Saudi Arabia, Zebrafish

PURPOSE: Leber congenital amaurosis (LCA) is one of the most severe eye dystrophies characterized by severe vision loss at an early stage and accounts for approximately 5% of all retinal dystrophies. The purpose of this study was to identify a novel LCA disease allele or gene and to develop an approach combining genetic mapping with whole exome sequencing.METHODS: Three patients from King Khaled Eye Specialist Hospital (KKESH205) underwent whole genome single nucleotide polymorphism genotyping, and a single candidate region was identified. Taking advantage of next-generation high-throughput DNA sequencing technologies, whole exome capture sequencing was performed on patient KKESH205#7. Sanger direct sequencing was used during the validation step. The zebrafish model was used to examine the function of the mutant allele.RESULTS: A novel missense mutation in Bardet-Biedl syndrome 4 protein (BBS4) was identified in a consanguineous family from Saudi Arabia. This missense mutation in the fifth exon (c.253G>C;p.E85Q) of BBS4 is likely a disease-causing mutation as it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, or matching normal controls. Functional analysis of this mutation in zebrafish indicates that the G253C allele is pathogenic. Coinjection of the G253C allele cannot rescue the mislocalization of rhodopsin in the retina when BBS4 is knocked down by morpholino injection. Immunofluorescence analysis in cell culture shows that this missense mutation in BBS4 does not cause obvious defects in protein expression or pericentriolar localization.CONCLUSIONS: This mutation likely mainly reduces or abolishes BBS4 function in the retina. Further studies of this allele will provide important insights concerning the pleiotropic nature of BBS4 function.

Alternate JournalMol Vis
PubMed ID22219648
PubMed Central IDPMC3250376
Grant ListF32 EY019430 / EY / NEI NIH HHS / United States
F32EY19430 / EY / NEI NIH HHS / United States
S10 RR026550 / RR / NCRR NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
R01 EY017037 / EY / NEI NIH HHS / United States
R01EY018571 / EY / NEI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
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