Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders

Item Type:	Article
Title:	Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders
Creators Name:	Ravindran, E. and Jühlen, R. and Vieira-Vieira, C.H. and Ha, T. and Salzberg, Y. and Fichtman, B. and Luise-Becker, L. and Martins, N. and Picker-Minh, S. and Bessa, P. and Arts, P. and Jackson, M.R. and Taranath, A. and Kamien, B. and Barnett, C. and Li, N. and Tarabykin, V. and Stoltenburg-Didinger, G. and Harel, A. and Selbach, M. and Dickmanns, A. and Fahrenkrog, B. and Hu, H. and Scott, H. and Kaindl, A.M.
Abstract:	Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) include a heterogeneous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities, and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic variants in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here, we report biallelic variants in NUP85 in two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS, thereby expanding the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 variants cause conformational changes that could have an effect on NPC architecture or on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs but unaltered nucleocytoplasmic compartmentalization, abnormal mitotic spindle morphology, and decreased cell viability and proliferation in one patient's cells. Our results also indicate the link of common cellular mechanisms involved in MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broaden the phenotypic spectrum of NUP85-linked human disease and propose a role for NUP85 in nervous system development.
Keywords:	Nephrotic Syndrome, Phenotype, Mutation, Genetic Disorder, Heterogeneity, Cell Survival, Genes, Microcephaly, Mitotic Spindle Apparatus, Nuclear Pore, Nuclear Pore Complex Proteins, Genetic Pedigree, Cognitive Impairment, Autosomal Recessive Inheritance, Short Stature, Nervous System Development, Seckel Syndrome, Nephrotic Syndrome, Steroid-Resistant, Merlob Syndrome, Congenital Facial Anomalies
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	30
Number:	22
Page Range:	2068-2081
Date:	15 November 2021
Additional Information:	Copyright © The Author(s) 2021. Published by Oxford University Press. All rights reserved.
Official Publication:	https://doi.org/10.1093/hmg/ddab160
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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