NUP107 – Galloway-Mowat Syndrome

Galloway-Mowat syndrome (GAMOS; MONDO:0009627) is an autosomal recessive neuro-renal disorder characterized by microcephaly, brain anomalies, and early-onset steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis (HP:0000252, HP:0012588, HP:0000097). Though biallelic WDR73 and KEOPS subunit mutations are established causes, NUP107 (HGNC:29914) has emerged as a key nucleoporin involved in centrosome positioning, spindle assembly, and nuclear pore complex integrity.

In two consanguineous Turkish families, five affected individuals harboring a homozygous NUP107 splice-site variant, c.303G>A (p.Met101Ile), displayed partial skipping of exon 4, reduced NUP107 protein levels, and diminished nuclear pore density in fibroblasts ([PMID:28280135]). This variant segregated with disease in all five cases in a classic autosomal recessive pattern, confirming biallelic inheritance of NUP107 loss-of-function.

An independent study identified an identical homozygous NUP107 mutation in four additional GAMOS-like families, expanding the cohort to nine affected individuals and underscoring recurrence across diverse pedigrees ([PMID:30427554]). These families exhibited early-onset nephrotic syndrome and microcephaly, mirroring the core GAMOS phenotype and reinforcing genotype–phenotype correlation.

Autosomal recessive inheritance of biallelic NUP107 variants has been confirmed by segregation analysis in two consanguineous kindreds and recurrence in four independent pedigrees, totaling nine probands with GAMOS features. No heterozygous carriers exhibit clinical signs, consistent with a loss-of-function mechanism.

Functional assessment in patient-derived fibroblasts demonstrated that c.303G>A (p.Met101Ile) induces exon 4 skipping, leading to markedly reduced NUP107 and obligate partner NUP133 protein levels and decreased nuclear pore complex density ([PMID:28280135]). These cellular defects are concordant with nuclear transport impairment and likely underlie neuronal and podocyte dysfunction in GAMOS.

Collectively, the genetic and experimental data support a Strong clinical validity for the NUP107–Galloway-Mowat syndrome association, with nine probands, multi-family segregation, and concordant functional evidence. NUP107 variant screening should be considered in patients with early-onset steroid-resistant nephrotic syndrome and microcephaly to inform diagnosis, genetic counseling, and potential future therapeutic strategies.

References

• Journal of medical genetics • 2017 • Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome. PMID:28280135
• Annals of neurology • 2018 • Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome. PMID:30427554

Evidence Based Scoring (AI generated)