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

Ethiraj Ravindran, Ramona Jühlen, Carlos H. Vieira-Vieira, Thuong Ha, Yuval Salzberg, Boris Fichtman, Lena Luise-Becker, Nuno Martins, Sylvie Picker-Minh, Paraskevi Bessa, Peer Arts, Matilda R. Jackson, Ajay Taranath, Benjamin Kamien, Christopher Barnett, Na Li, Victor Tarabykin, Gisela Stoltenburg-Didinger, Amnon Harel, Matthias SelbachAchim Dickmanns, Birthe Fahrenkrog, Hao Hu, Hamish Scott, Angela M. Kaindl

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)2068-2081
Number of pages14
JournalHuman Molecular Genetics
Volume30
Issue number22
DOIs
StatePublished - 1 Nov 2021

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© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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