Alternative titles; symbols
HGNC Approved Gene Symbol: ZMIZ1
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38): 10:79,068,966-79,316,519 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.3 | Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies | 618659 | Autosomal dominant | 3 |
The ZMIZ1 gene encodes a member of the PIAS (see 603566)-like family of proteins that interact with nuclear hormone receptors. It is a coactivator of several transcription factors, including TP53 (191170), NOTCH1 (190198), and AR (313700) (summary by Carapito et al., 2019).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (1999) cloned ZMIZ1, which they designated KIAA1224. RT-PCR ELISA detected ZMIZ1 expression in all tissues and specific brain regions examined. Highest expression was in heart, ovary, and brain. Within brain, highest expression was in amygdala.
By 5-prime RACE of brain and prostate cDNA libraries to extend the partial KIAA1224 cDNA, Sharma et al. (2003) obtained full-length RAI17, which they designated ZIMP10. The deduced 1,067-amino acid protein has a calculated molecular mass of 123 kD. RAI17 contains an MSX (see 123101)-interacting zinc finger (MIZ) domain, a nuclear localization signal sequence, and 2 proline-rich regions. In vitro transcription and translation resulted in a protein with an apparent molecular mass of 130 kD. Northern blot analysis detected a 7.2-kb transcript expressed most abundantly in ovary, with lower levels in prostate, spleen, and testis. Expression was also detected in various cancer cell lines. There was little to no expression in thymus, small intestine, colon, and peripheral blood leukocytes. RAI17 colocalized with endogenous androgen receptor (AR; 313700) in the nuclei of prostate epithelial cells from human tissue samples.
Using whole-mount in situ hybridization, Rodriguez-Magadan et al. (2008) found that Zimp7 (ZMIZ2; 611196) and Zimp10 were extensively expressed in partially overlapping patterns from embryonic day 7.5 (E7.5) to midgestation in mouse embryo. Expression of Zimp7 and Zimp10 predominated in neural tissues at early stages and dropped at E12.5.
Sharma et al. (2003) determined that the ZMIZ1 gene contains 21 exons.
By genomic sequence analysis, Sharma et al. (2003) mapped the ZMIZ1 gene to chromosome 10q22.1-q22.3.
Sharma et al. (2003) showed a direct interaction between RAI17 and AR by cotransfection and immunoprecipitation of simian kidney cell lysates. The transactivation domain of AR and the central region of RAI17 were responsible for the interaction. A strong intrinsic transactivation domain was identified in the C-terminal proline-rich region of RAI17. In human prostate cancer cells, RAI17 augmented the transcriptional activity of AR. Moreover, RAI17 colocalized with AR and SUMO1 (UBL1; 601912) at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo. Studies using sumoylation-deficient AR mutants suggested that the augmentation of AR activity by RAI17 is dependent on the sumoylation of the receptor. Sharma et al. (2003) concluded that RAI17 is a coregulator of AR.
Pinnell et al. (2015) found that conditional Zmiz1 knockout in mice inhibited T-cell development and transiently induced goblet-cell hyperplasia, similar to deletion of Notch1 (190198). RT-PCR analysis showed that Zmiz1 deletion caused a significant reduction in transcripts of Notch target genes, demonstrating that Zmiz1 and Notch1 have converging roles during T-cell development. However, unlike Notch1, Zmiz1 inactivation did not affect intestinal homeostasis or myeloid suppression, indicating their diverging functions outside of the T-cell lineage. Transplantation studies revealed that Zmiz1 was important for initiation and maintenance of Notch-induced T-cell acute lymphoblastic leukemia (T-ALL). Chromatin immunoprecipitation- and RNA-sequencing analyses demonstrated that Zmiz1 and Notch1 cooperatively recruited each other to chromatin through direct binding of the tetratricopeptide repeat domain of Zmiz1 to the RAM domain of Notch1. ZMIZ1 selectively regulated a subset of NOTCH1 target genes, particularly MYC, in both mouse and human T-ALL, and bound a unique class of NOTCH1 regulatory sites.
In 14 unrelated patients with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified de novo heterozygous mutations in the ZMIZ1 gene (see, e.g., 607159.0001-607159.0005). Three adopted sibs with a similar phenotype and a heterozygous mutation were also identified (607159.0006). The patients were ascertained through a transatlantic collaborative effort; the mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. None of the variants were found in available public databases, including gnomAD. The mutations, which included missense, frameshift, and splice site defects, were scattered throughout the gene, although there was a cluster of variants affecting a conserved alanine-rich region (residues 280-305) thought to have important functions. Analysis of peripheral blood from 5 patients showed normal mRNA levels, even for a patient with a splice site mutation, and expression of 3 missense variants into HeLa cells showed proper nuclear localization. Transfection of 3 variants (T300M, 607159.0001; c.3112dupA, 607159.0002; and K91R, 607159.0003) into HEK293T cells resulted in decreased induction of luciferase activity compared to wildtype (although the change for K91R was not statistically significant), suggesting impaired coactivation activity of the mutant proteins. Electroporation of these 3 mutants into progenitor cells in the ventricular zone of embryonic mice cortices resulted in defective neuronal migration to the cortex, as well as morphologic abnormalities of the neurons manifest as rounded cells with aberrantly oriented processes. These findings suggested that the ZMIZ1 mutations disrupted proper neuronal polarization and neuronal migration in the developing cortex. Functional studies of the other variants and additional studies of patient cells were not performed.
In 2 unrelated patients (patients 1 and 4) with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified a de novo heterozygous c.899C-T transition (c.899C-T, NM_020338) in the ZMIZ1 gene, resulting in a thr300-to-met (T300M) substitution in a conserved alanine/threonine-rich region. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Analysis of patient cells showed normal mRNA levels, and transfection of the mutation into HeLa cells showed nuclear localization of the mutant protein.
In a 12-year-old girl (patient 3) with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified a de novo heterozygous 1-bp duplication (c.3112dupA, NM_020338) in the ZMIZ1 gene, resulting in a frameshift and premature termination (Thr1038AsnfsTer4) in the C-terminal transactivation domain. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Transfection of the mutation into HeLa cells showed nuclear localization of the mutant protein. (The mutation designation is based on table 1 and a corrected table S1 in the article by Carapito et al. (2019).)
In a 3-year-old girl (patient 7) with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified a de novo heterozygous c.272A-G transition (272A-G, NM_020338) in the ZMIZ1 gene, resulting in a lys91-to-arg (K91R) substitution at a SUMO acceptor site. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Transfection of the mutation into HeLa cells showed nuclear localization of the mutant protein. (The mutation designation is based on table 1 and a corrected table S1 in the article by Carapito et al. (2019).)
In an 8-year-old girl (patient 9) with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified a de novo heterozygous c.887C-A transversion (c.887C-A, NM_020338) in the ZMIZ1 gene, resulting in a thr296-to-lys (T296K) substitution in a conserved alanine/threonine-rich region. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. (The mutation designation is based on table 1 and a corrected table S1 in the article by Carapito et al. (2019).)
In a 1-year-old boy (patient 11) with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified a de novo heterozygous A-to-G transition (c.3097-2A-G, NM_020338) in the last intron (intron 24) of the ZMIZ1 gene, resulting in a splice site alteration and the production of 2 aberrant transcripts. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Analysis of patient cells showed normal mRNA levels. (The mutation designation is based on table 1 and a corrected table S1 in the article by Carapito et al. (2019).)
In 3 sibs (patients 13, 14, and 15) with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA; 618659), Carapito et al. (2019) identified a heterozygous 1-bp duplication (c.1386dupC, NM_020338) in the ZMIZ1 gene, resulting in a frameshift and premature termination (Thr463HisfsTer14). The patients were adopted; no parental DNA was available. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. (The mutation designation is based on table 1 and a corrected table S1 in the article by Carapito et al. (2019).)
Carapito, R., Ivanova, E. L., Morlon, A., Meng, L., Molitor, A., Erdmann, E., Kieffer, B., Pichot, A., Naegely, L., Kolmer, A., Paul, N., Hanauer, A., and 49 others. ZMIZ1 variants cause a syndromic neurodevelopmental disorder. Am. J. Hum. Genet. 104: 319-330, 2019. Note: Erratum: Am. J. Hum. Genet. 106: 137 only, 2020. [PubMed: 30639322] [Full Text: https://doi.org/10.1016/j.ajhg.2018.12.007]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Pinnell, N., Yan, R., Cho, H. J., Keeley, T., Murai, M. J., Liu, Y., Alarcon, A. S., Qin, J., Wang, Q., Kuick, R., Elenitoba-Johnson, K. S. J., Maillard, I., Samuelson, L. C., Cierpicki, T., Chiang, M. Y. The PIAS-like coactivator Zmiz1 is a direct and selective cofactor of Notch1 in T cell development and leukemia. Immunity 43: 870-883, 2015. [PubMed: 26522984] [Full Text: https://doi.org/10.1016/j.immuni.2015.10.007]
Rodriguez-Magadan, H., Merino, E., Schnabel, D., Ramirez, L., Lomeli, H. Spatial and temporal expression of Zimp7 and Zimp10 PIAS-like proteins in the developing mouse embryo. Gene Expr. Patterns 8: 206-2213, 2008. [PubMed: 18053775] [Full Text: https://doi.org/10.1016/j.modgep.2007.10.005]
Sharma, M., Li, X., Wang, Y., Zarnegar, M., Huang, C.-Y., Palvimo, J. J., Lim, B., Sun, Z. hZimp10 is an androgen receptor co-activator and forms a complex with SUMO-1 at replication foci. EMBO J. 22: 6101-6114, 2003. [PubMed: 14609956] [Full Text: https://doi.org/10.1093/emboj/cdg585]