NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron

Abstract

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.

Keywords: NUP85; developmental delay; epileptic spasm; microcephaly; nephrotic syndrome type 17; steroid-resistant nephrotic syndrome.

Figure 1

Molecular pathways of NUP85 interactions (created using BioRender.com, accessed on 14 September 2023).

Figure 2

Electroencephalogram (EEG) performed at 4.6 months displays an interictal hypsarrhythmic pattern and ictal EEG (spasm) with a high-voltage slow wave followed by low and fast activity.

Figure 3

Brain magnetic resonance imaging (MRI) performed at 2.5 years old. (A) A midline sagittal T2-weighted Fast Spin-Echo (FSE) image shows mild corpus callosum (CC) hypoplasia with prevalent involvement of the CC trunk (arrows). (B) Diffusion Tensor Imaging (DTI) Tractography with CC (red color) fiber tracking. (C) An Axial Fluid-Attenuated Inversion Recovery (FLAIR) image displays bilateral paratrigonal white matter hyperintensity (arrowheads). (D) Simplified gyration of the cerebral cortex.

Figure 4

NUP85 protein conservation across species; note the high conservation of mutated residues identified in this study.