Novel biallelic <i>NUP107</i> variants affect the nuclear pore complex and expand the clinical spectrum to include brain malformations.

Abstract

Biallelic variants in <i>NUP107</i> cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with syndromic SRNS have microcephaly, developmental delay or intellectual disability and short stature. Simplified gyration is observed in some individuals. We report on a 2-year-old girl with novel biallelic <i>NUP107</i> variants, c.2606G>T; p.(Gly869Val) and c.1576+1G>A, proteinuria and a severe neurodevelopmental disorder with microcephaly, developmental delay, early-onset seizures, sensorineural hearing loss and brain structural anomalies, including simplified gyral pattern and hypoplasia of the corpus callosum, pons, brainstem and cerebellum. NUP107 is part of the NUP107-160 complex, which, together with other proteins termed nucleoporins, forms the nuclear pore complex (NPC). The NPC regulates nucleocytoplasmic transport and other cellular processes. In patient-derived fibroblasts, we identified aberrantly spliced <i>NUP107</i> mRNAs with a frameshift and premature stop codon leading to non-sense-mediated mRNA decay, reduced levels of <i>NUP107</i> transcripts, reduced NUP107 and NUP133 proteins, and a reduced NPC number. In addition, an abnormal nucleolar morphology was found in patient-derived cells. Our functional data support the conclusion that the <i>NUP107</i> variants underlie the patient's phenotype, thereby broadening the clinical spectrum associated with <i>NUP107</i> variants to include abnormal brain development.