Homozygous mutation in <i>NUP107</i> leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.

Abstract

Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in <i>WDR73</i> (OMIM: 616144). However, not all patients harbour demonstrable <i>WDR73</i> deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology. 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. 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 <i>nucleoporin, 107-KD</i> (<i>NUP107</i>). 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. Recently, <i>NUP107</i> was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other <i>NUP107</i>-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for <i>NUP107</i> in the regulation of brain growth and a GAMOS-like presentation.