ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

TitleZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.
Publication TypeJournal Article
Year of Publication2019
AuthorsCarapito, R, Ivanova, EL, Morlon, A, Meng, L, Molitor, A, Erdmann, E, Kieffer, B, Pichot, A, Naegely, L, Kolmer, A, Paul, N, Hanauer, A, Mau-Them, FTran, Jean-Marçais, N, Hiatt, SM, Cooper, GM, Tvrdik, T, Muir, AM, Dimartino, C, Chopra, M, Amiel, J, Gordon, CT, Dutreux, F, Garde, A, Thauvin-Robinet, C, Wang, X, Leduc, MS, Phillips, M, Crawford, HP, Kukolich, MK, Hunt, D, Harrison, V, Kharbanda, M, Smigiel, R, Gold, N, Hung, CY, Viskochil, DH, Dugan, SL, Bayrak-Toydemir, P, Joly-Helas, G, Guerrot, A-M, Schluth-Bolard, C, Rio, M, Wentzensen, IM, McWalter, K, Schnur, RE, Lewis, AM, Lalani, SR, Mensah-Bonsu, N, Céraline, J, Sun, Z, Ploski, R, Bacino, CA, Mefford, HC, Faivre, L, Bodamer, O, Chelly, J, Isidor, B, Bahram, S
Corporate AuthorsDeciphering Developmental Disorders Study, University of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2019 02 07
KeywordsAlleles, Animals, Child, Child, Preschool, Developmental Disabilities, Female, Humans, Infant, Intellectual Disability, Male, Mice, Point Mutation, Syndrome, Transcription Factors

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID30639322
PubMed Central IDPMC6369415
Grant ListR01 CA070297 / CA / NCI NIH HHS / United States
R01 CA166894 / CA / NCI NIH HHS / United States
U01 HG007301 / HG / NHGRI NIH HHS / United States
R01 NS069605 / NS / NINDS NIH HHS / United States
R01 DK104941 / DK / NIDDK NIH HHS / United States
R01 CA151623 / CA / NCI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R56 NS069605 / NS / NINDS NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
UM1 HG007301 / HG / NHGRI NIH HHS / United States