ZMIZ1 (HGNC: 16493) located on 10q22, encodes a member of the PIAS (protein inhibitor of activated STAT) family of proteins. The protein acts as transcriptional coactivator in the TGF-beta signaling pathway by increasing the activity of the SMAD3/SMAD4 transcriptional complex (PMID:16777850). It is also involved in the transcriptional activation of a subset of NOTCH1 target genes including MYC, thymocyte and T cell development and in the regulation of postmitotic positioning of pyramidal neurons in the developing cerebral cortex (PMID:30639322). ZMIZ1 variants have been detected in a dozen of unrelated patients from different groups and in both sexes with common clinical features of neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (OMIM #607159). Associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, various other congenital malformations (PMID: 30639322; 31833199, 34680978). ZMIZ1 variants carriers show diverse phenotypes and being affected in multiple organs, thus ZMIZ1 is lumped to Complex neurodevelopmental disorder (MONDO:0100038). Identified ZMIZ1 variants show mostly de novo (PMID: 30639322; 35432459). In some cases, however, ZMIZ1 are found to be inherited from the parents (PMID: 34680978; 31833199). ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning (PMID: 30639322). Based on the consistent phenotypes; sufficient genetic and experimental evidence, ZMIZ1 is curated as “Definitive” for Complex neurodevelopmental disorder.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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