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Bardet–Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172mutations were initially reported in Jeune and Mainzer–Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet–Biedl-like ciliopathy. This is the second report of IFT172mutations in BBS patients validating IFT172as the twentieth BBS gene (BBS20). Moreover, another IFTgene, IFT27, was already associated with BBS, confirming the implication of IFTgenes in the pathogenesis of BBS.

Expression profile analysis clusters Gpnmbwith known pigment genes, Tyrp1, Dct, and Si. During development, Gpnmbis expressed in a pattern similar to Mitf, Dctand Siwith expression vastly reduced in Mitfmutant animals. Unlike Dctand Si, Gpnmbremains expressed in a discrete population of caudal melanoblasts in Sox10-deficient embryos. To understand the transcriptional regulation of Gpnmbwe performed a whole genome annotation of 2,460,048 consensus MITF binding sites, and cross-referenced this with evolutionarily conserved genomic sequences at the GPNMB locus. One conserved element, GPNMB-MCS3, contained two MITF consensus sites, significantly increased luciferase activity in melanocytes and was sufficient to drive expression in melanoblasts in vivo. Deletion of the 5'-most MITF consensus site dramatically reduced enhancer activity indicating a significant role for this site in Gpnmbtranscriptional regulation. Future analysis of the Gpnmblocus will provide insight into the transcriptional regulation of melanocytes, and Gpnmbexpression can be used as a marker for analyzing melanocyte development and disease progression.