Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly

Abstract

Nucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85 was linked to childhood-onset steroid-resistant nephrotic syndrome (SRNS) in four affected individuals with intellectual disability but no microcephaly. Recently, we broaden the phenotype spectrum of NUP85-associated disease by reporting NUP85 variants in two unrelated individuals with primary autosomal recessive microcephaly (MCPH) and Seckel syndrome (SCKS) spectrum disorders (MCPH-SCKS) without SRNS. In this study, we report compound heterozygous NUP85 variants in an index patient with only MCPH phenotype, but neither Seckel syndrome nor SRNS was reported. We showed that the identified missense variants cause reduced cell viability of patient-derived fibroblasts. Structural simulation analysis of double variants is predicted to alter the structure of NUP85 and its interactions with neighboring NUPs. Our study thereby further expands the phenotypic spectrum of NUP85-associated human disorder and emphasizes the crucial role of NUP85 in the brain development and function.

SMPD4mediated sphingolipid metabolism regulates brain and primary cilia development

“…Delays in nuclear pore complex insertion and envelope closure were seen with SMPD4 knockdown (Smits et al ., 2023). Nuclear pore formation defects and variants in nuclear pore proteins are known to cause microcephaly (Carapito et al, 2019; Fujita et al, 2018; Ravindran et al, 2021; Ravindran et al, 2023; Rosti et al, 2017; Sandestig et al, 2020). Nucleoporin proteins localize to the base of the primary cilium in addition to the nuclear envelope (Kee et al, 2012).…”

NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron

“…Specifically, brain MRI abnormalities included delayed myelination, complete agenesis and/or hypoplasia of the corpus callosum, grey matter heterotopia, cortical malformation of the left frontal lobe, the absence of the cingulate gyrus, and simplified gyration of the cerebral cortex (refer to Table 1 for additional clinical details). These results can be largely explained by functional studies that revealed how the kind of mutation, such as hypomorphic and/or loss of function, led to variable severity phenotypes [29]. Specifically, missense variants affecting conserve residues of NUP85 impaired the protein function and its interaction with substrates, with distinct and organ-specific consequences [18,29].…”

“…These results can be largely explained by functional studies that revealed how the kind of mutation, such as hypomorphic and/or loss of function, led to variable severity phenotypes [29]. Specifically, missense variants affecting conserve residues of NUP85 impaired the protein function and its interaction with substrates, with distinct and organ-specific consequences [18,29]. Missense mutations p.Ala581Pro and p.Arg645Trp and splice site mutation c.405+1G>A of NUP85 were reported to prevent the interaction between NUP85 protein and its binding partner NUP160 and were associated with SRNS.…”

“…Moreover, the truncating mutation p.Arg107Cysfs*15 of NUP85 led to a complete loss of function of the protein with early lethality, neurodevelopment impairment, and embryonal death in zebrafish models. Concurrently, mutations affecting the interaction of the NUP85 protein with cytoskeletal proteins and components of mitotic machinery during brain developmental stages led to a neurological phenotype including microcephaly, developmental delay, and epilepsy [19,29].…”

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

“…Mutations in constituents of NUP107-160 complex have also been correlated to several developmental disorders. In this context, biallelic mutations in NUP85 (Table 2) have been linked to microcephaly (MCPH) and Seckel syndrome spectrum disorders (MCPH-SCKS; [96,97]). MCPH-SCKS includes a inhomogeneous group of diseases characterised by primary microcephaly with otherwise normal brain appearance and other variable findings including cognitive impairment, short stature, and abnormal facial features (facial dysmorphism) [98].…”