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ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

Authors :
Carapito, Raphael
Ivanova, Ekaterina L.
Morlon, Aurore
Meng, Linyan
Molitor, Anne
Erdmann, Eva
Kieffer, Bruno
Pichot, Angélique
Naegely, Lydie
Kolmer, Aline
Paul, Nicodème
Hanauer, Antoine
Tran Mau-Them, Frédéric
Jean-Marçais, Nolwenn
Hiatt, Susan M.
Cooper, Gregory M.
Tvrdik, Tatiana
Muir, Alison M.
Dimartino, Clémantine
Chopra, Maya
Source :
American Journal of Human Genetics. Feb2019, Vol. 104 Issue 2, p319-330. 12p.
Publication Year :
2019

Abstract

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro , ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo , overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00029297
Volume :
104
Issue :
2
Database :
Academic Search Index
Journal :
American Journal of Human Genetics
Publication Type :
Academic Journal
Accession number :
134530588
Full Text :
https://doi.org/10.1016/j.ajhg.2018.12.007