Background Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in WDR73 (OMIM: 616144). However, not all patients harbour demonstrable WDR73 deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology.
Methods Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function.
Results In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in nucleoporin, 107-KD (NUP107). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells.
Conclusion Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation.
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Contributors ADY, ADA, HK, IB, MT, ROR and UA identified subjects for study; BNS, DM JLS, ROR, SLB, SI, WT identified genetic variants and performed cell culture and sequence analysis; ROR, GB and IM-V contributed to the clinical interpretation and helped write the manuscript; SFN performed SNP analysis and interpretation; HK and JGG supervised the project.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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