Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly

Abstract

The ciliopathies are an expanding group of disorders caused by mutations in genes implicated in the biogenesis and function of primary cilia. Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by progressive retinal degeneration, obesity, polydactyly, cognitive impairment, kidney anomalies and hypogonadism. Mutations in SDCCAG8(NPHP10) were described recently in patients with nephronophthisis and retinal degeneration (Senior-Loken syndrome; SLS). Given the phenotypic and genetic overlap between known ciliopathy genes, we hypothesized that mutations in SDCCAG8 might also contribute alleles to more severe, multisystemic ciliopathies. We performed genetic and phenotypic analyses of 2 independent BBS cohorts. Subsequent to mutation screening, we made a detailed phenotypic analysis of 5 families mutated for SDCCAG8 (3 homozygous and 2 compound heterozygous mutations) and conducted statistical analyses across both cohorts to examine possible phenotype-genotype correlations with mutations at this locus. All patients with mutations in SDCCAG8 fulfilled the diagnostic criteria for BBS (retinal degeneration, obesity, cognitive defects, renal failure, hypogonadism). Interestingly, none of the patients with primary SDCCAG8 mutations had polydactyly, a frequent but not obligatory BBS feature. In contrast, the same patients displayed early-onset renal failure, obesity, as well as recurrent pulmonary and ENT infections. Comparison of the phenotypes of these families with our entire BBS cohort indicated that renal impairment and absent polydactyly correlated significantly with causal SDCCAG8 mutations. Thus, SDCCAG8 mutations are sufficient to cause BBS in 1–2% of our combined cohorts, and define this gene as the sixteenth BBS locus (BBS16). The absence of polydactyly and the concomitant, apparently fully penetrant association with early kidney failure represents the first significant genotype-phenotype correlation in BBS that potentially represents an indicator for phenotype-driven priority screening and informs specific patient management.

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

“…NPHS2 and SDCCAG8 are known to be involved in nondiabetic nephropathy susceptibility, with critical roles in FSGS/glomerulosclerosis and Bardet Biedl syndrome, respectively; BMP pathway genes have recently been implicated in DKD (68)(69)(70)(71). Significantly different effects for the APOL1 second-gene interaction on the basis of presence of two APOL1 risk variants (versus less than two) were seen for all 14 interactive genes (67).…”

Renal-Retinal Ciliopathy Gene Sdccag8 Regulates DNA Damage Response Signaling

“…3,4 Because several of the clinical features are shared with BBS, with the exception of the absence of polydactyly, individuals with SDCCAG8 mutations are also considered as part of the BBS spectrum. 3,4 SDCCAG8 encodes a coiled-coil domain protein with no additional conserved domains.…”

“…3,4 Because several of the clinical features are shared with BBS, with the exception of the absence of polydactyly, individuals with SDCCAG8 mutations are also considered as part of the BBS spectrum. 3,4 SDCCAG8 encodes a coiled-coil domain protein with no additional conserved domains. 5 The protein localizes to the centrioles throughout the cell cycle, 3,5 to the basal body of cilia, and also to the spermatocytes in the rat testis.…”

The role of primary cilia in the development and disease of the retina

“…203 NPHP4 mutations lead to nephronophthisis (NPHP) and RP, 204 and SDCCAG8 is mutated in BBS and a retinal-renal ciliopathy. [205][206][207] Mutations in the homolog of RPGRIP, RPGRIP1L, are also associated with a suite of disorders involving retinal dystrophy, including JBTS, 208 MKS and cerebello-oculo-renal syndrome (CORS). 209 A specific mutation in RPGRIP1L has been shown to be a modifier of retinal phenotype in these syndromic ciliopathies.…”