NPHP1 – Bardet-Biedl syndrome

Nephrocystin-1, encoded by NPHP1, is a ciliary transition zone protein classically associated with nephronophthisis. Emerging data implicate biallelic NPHP1 mutations in Bardet-Biedl syndrome (BBS), a phenotypically overlapping ciliopathy characterized by rod-cone dystrophy, polydactyly, obesity, developmental delay and renal anomalies. Genetic and functional studies have begun to clarify this association and its diagnostic relevance.

BBS due to NPHP1 follows an autosomal‐recessive inheritance pattern. A recurrent 290 kb homozygous deletion segregated with classical BBS in one family ([PMID:24746959]). In the same cohort, five independent families carried a conserved missense variant, c.14G>T (p.Arg5Leu), always in trans with pathogenic alleles at other BBS loci and enriched in Hispanic pedigrees ([PMID:24746959]). Segregation data include two affected siblings with the homozygous deletion.

Variant spectrum comprises large homozygous deletions and rare SNVs. The founder‐enriched missense allele c.14G>T (p.Arg5Leu) represents a recurrent hypomorphic variant in oligogenic BBS, while the 290 kb exon 4–20 deletion behaves as a primary pathogenic allele under an AR model.

Functional assays support a loss‐of‐function mechanism. In zebrafish, suppression of nphp1 exacerbates phenotypes when combined with primary BBS mutations, indicating a modifier and primary role ([PMID:24746959]). Biochemically, nephrocystin-1’s SH3 domain binds the polyproline motif of polycystin-1, regulating apoptotic responses and ciliary trafficking in renal cells, linking NPHP1 dysfunction to ciliopathy phenotypes ([PMID:20856870]).

However, a zebrafish crispant model of TZ genes shows variable phenotypic penetrance and transient defects that partially resolve over time, underscoring phenotypic plasticity and model limitations ([PMID:36533556]).

Together, these data provide limited but growing evidence that NPHP1 can be a primary AR cause of BBS. Routine inclusion of NPHP1 in BBS gene panels may uncover rare cases and guide genetic counseling. Key take-home: Screening for NPHP1 CNVs and SNVs can reveal rare AR contributions to BBS and inform molecular diagnosis.

References

• American journal of human genetics • 2014 • Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome. PMID:24746959
• PloS one • 2010 • Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. PMID:20856870
• Disease models & mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. PMID:36533556

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