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

ABSTRACT: Primary autosomal recessive microcepahly and Seckel syndrome spectrum disodrers (MCPH-SCKS) include a heterogenous 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 mutations in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here we report that homozygous mutations in NUP85 can also cause MCPH-SCKS without SRNS and thereby expand the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 mutation to have neither an effect on NPC architecture nor on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs, abnormal mitotic spindle morphology, altered expression levels of protein involved in of cytoskeletal dynamics and decreased cell viability in patient cells. These altered biological processes can explain the disease-causative nature of the mutant NUP85 associated with the human phenotype. Our results also indicates the link of common cellular mechanism involved in the MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broadened the phenotype spectrum of NUP85-specific human disease and emphasizes a role of NUP85 in the development of the nervous system.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Fibroblast

DISEASE(S): Seckel Syndrome,Primary Autosomal Recessive Microcephaly

SUBMITTER: Carlos Henrique Vieira e Vieira  

LAB HEAD: Matthias Selbach

PROVIDER: PXD018838 | Pride | 2022-08-11

REPOSITORIES: Pride