Alternative titles; symbols
HGNC Approved Gene Symbol: ZMYM3
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:71,239,624-71,255,290 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Intellectual developmental disorder, X-linked 112 | 301111 | X-linked recessive | 3 |
ZMYM3 contains a DUF3504 domain, related to the tyrosine recombinase (YR) element of Crypton DNA transposons present in lower organisms. The DUF3504 domain is derived from the YR element of Cryptons but lacks the complete catalytic tetrad essential for YR activity. Proteins that contain a DUF3504 domain function as transcriptional activators or repressors (Kojima and Jurka, 2011).
Van der Maarel et al. (1996) reported the cloning and characterization of a gene, which they called DXS6673E, that was disrupted by a balanced X;13 translocation in a female with mental retardation. They identified a YAC clone that spanned the breakpoint and used this YAC to isolate a cDNA from a fetal brain library. The cDNA encodes a predicted 1,358-amino acid polypeptide. By Northern blot analysis, they showed that DXS6673E is highly conserved among vertebrates and that its expression is most abundant in brain. Van der Maarel et al. (1996) demonstrated that DXS6673E is subject to X inactivation.
Scheer et al. (2000) cloned mouse Zmym3, which they called Dxhxs6673e. The 2 major Zmym3 transcripts contain 24 common exons and differ in their noncoding first exons. Both encode a deduced 1,370-amino acid protein with 5 predicted zinc finger motifs, 5 nuclear localization signals of the SV40 large T antigen type, a bipartite nuclear localization signal, and 3 putative sites for tyrosine phosphorylation. A central proline-rich region contains 2 putative SH3-binding sites. RT-PCR revealed extensive alternative splicing of 5-prime Zmym3 exons in both major transcripts, but after exon 5, only exon 23 was subject to alternative splicing. Northern blot analysis detected expression of a major Zmym3 transcript in mouse embryos at all developmental stages examined and in all adult mouse tissues examined, with highest expression in brain and testis. RT-PCR showed that some Zmym3 variants were expressed at only specific developmental stages or in specific tissues. Fluorescence-tagged Zmym3 isoforms were expressed in both cytoplasm and nucleus, but not in nucleolus, in a cell type-specific manner. Orthologs of Zmym3 were detected in vertebrates and D. melanogaster, but not in C. elegans, and several features of mouse Zmym3 were conserved in the human ortholog.
Using database analysis to identify Crypton-related proteins, Kojima and Jurka (2011) identified ZMYM3. The deduced protein has a central MYM-type zinc finger domain, followed by a proline-rich region, and a C-terminal 315-amino acid DUF3504 domain. The DUF3504 domain of ZMYM3 is very similar to that of ZMYM2 (602221) and ZMYM4 (613568). Orthologs of ZMYM proteins were detected in vertebrates, and more distantly in chordates and invertebrates.
Van der Maarel et al. (1996) reported that the ZNF261 gene contains 26 exons, including 2 putative alternatively spliced noncoding first exons (1A and 1B).
Van der Maarel et al. (1996) mapped the ZNF261 gene to chromosome Xq13.1.
Scheer et al. (2000) mapped the mouse Zmym3 gene to a region of chromosome XC-D that shares homology of synteny with human chromosome Xq13.
Hakimi et al. (2003) identified a family of multiprotein corepressor complexes that function through modifying chromatin structure to keep genes silent. The polypeptide composition of these complexes includes a common core of 2 subunits, HDAC1 (601241)/HDAC2 (605164) and the FAD-binding protein BHC110 (AOF2; 609132). Other subunits of these complexes include ZNF261, GTF2I (601679), and polypeptides associated with cancer-causing chromosomal translocations.
Kojima and Jurka (2011) determined that the ancestral gene of Drosophila Woc and mammalian ZMYM genes originated in the common ancestor of all bilaterians more than 910 million years ago, and represents the third-oldest transposon domestication event known, following those that generated TERT (187270) and PRP8 (607300). The ZMYM2, ZMYM3, and ZMYM4 genes were duplicated from a single gene during 2 rounds of whole-genome duplication in the early evolution of vertebrates, before the split between agnathans and jawed vertebrates.
Van der Maarel et al. (1996) reported a mentally retarded female whose ZNF261 gene was disrupted in the 5-prime UTR by a balanced X;13 translocation. They noted that apart from mental retardation, the only conspicuous clinical features in this patient were scoliosis and spotty abdominal hypopigmentation.
In 3 Finnish brothers with X-linked intellectual developmental disorder (XLID112; 301111), Philips et al. (2014) identified a missense mutation in the ZMYM3 gene (R441W; 300061.0001) at a highly conserved residue. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, was present in the unaffected mother. Functional studies of the variant were not performed, but Philips et al. (2014) hypothesized that the mutation may disturb a zinc finger domain known to bind DNA.
In 27 individuals (24 males and 3 females) with XLID112 from 25 unrelated families, Hiatt et al. (2023) identified 22 different hemizygous or heterozygous mutations in the ZMYM3 gene (see, e.g., 300061.0001-300061.0003). All of the mutations occurred at highly conserved positions. The mutations were inherited from heterozygous unaffected mothers in 17 males and arose de novo in 4 males; inheritance was not established for 3 males. Mutations in 26 individuals were missense. All variants were rare, with no hemizygous males or homozygous females observed in the gnomAD database. Among the 3 females, 2 mutations occurred de novo and 1 mutation was inherited from her apparently unaffected mother. X-inactivation studies were performed in 2 of these females. Skewed X-inactivation (97%) was seen in one of the females (individual 20), who had a de novo R1294C mutation (300061.0003). In the female (individual 18) with the maternally inherited mutation (Leu226TrpfsTer8), skewing was abnormal (greater than 94%) in both the affected daughter and her unaffected heterozygous mother, raising the possibility that this allele with predicted loss of function is benign.
In 3 Finnish half brothers (family D222) mild X-linked intellectual developmental disorder (XLID112; 301111), Philips et al. (2014) identified a c.1321C-T transition (c.1321C-T, NM_201599.2) in exon 7 of the ZMYM3 gene, resulting in an arg441-to-trp (R441W) substitution at a highly conserved residue. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, was present in the unaffected mother. It was screened against the dbSNP (build 138), Exome Variant Server, and in-house exome databases, and was not found in 100 Finnish blood donors or in an unaffected brother. Functional studies of the variant were not performed, but Philips et al. (2014) hypothesized that the mutation may disturb a zinc finger domain known to bind DNA. All 3 patients had mildly impaired intellectual development, 2 had hypospadias, 2 had a bicuspid aortic valve, 2 had ADHD, and 1 had microcephaly (-3 SD).
In a 4-year-old boy (individual 22) with XLID112, Hiatt et al. (2023) identified hemizygosity for the R441W mutation in the ZMYM3 gene. The patient had mild global developmental delay, triangular face, prominent forehead, long eyelashes, and mild short stature. Other family members were not tested.
In 3 unrelated boys (individuals 6, 7, and 8) with X-linked intellectual developmental disorder-112 (XLID112; 301111), Hiatt et al. (2023) identified hemizygosity for a c.1332G-A transition (c.1332G-A, NM_005096.3) in the ZMYM3 gene, resulting in an arg441-to-gln (R441Q) substitution. The variant was inherited from heterozygous mothers without intellectual disability (one had a history of learning disability and one had attention deficit-hyperactivity disorder). All 3 boys had speech delay, motor delay, traits consistent with autism spectrum disorder, behavioral problems, and dysmorphic facial features. All 3 had genitourinary anomalies (one with a single renal cyst, one with cryptorchidism and enuresis, and one with hypospadias and ambiguous genitalia). Two of the 3 had short stature.
In a 5-year-old girl (individual 20) with X-linked intellectual developmental disorder-12 (XLID112; 301111), Hiatt et al. (2023) identified a de novo heterozygous c.3880C-T transition (c.3880C-T, NM_005096.3) in the ZMYM3 gene, resulting in an arg1294-to-cys (R1294C) substitution. The girl had global developmental delay, mild microcephaly, dysmorphic facial features including synophrys, thin lips, and protruding ears, pyelectasis, volvulus of midgut, and pancreatic cysts. Significantly skewed X-inactivation (97%) was seen. Hiatt et al. (2023) also identified this mutation in hemizygosity in a male fetus (individual 16) in a pregnancy terminated at 22 weeks' gestation.
Hakimi, M.-A., Dong, Y., Lane, W. S., Speicher, D. W., Shiekhattar, R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 278: 7234-7239, 2003. [PubMed: 12493763] [Full Text: https://doi.org/10.1074/jbc.M208992200]
Hiatt, S. M., Trajkova, S., Sebastiano, M. R., Partridge, E. C., Abidi, F. E., Anderson, A., Ansar, M., Antonarakis, S. E., Azadi, A., Bachmann-Gagescu, R., Bartuli, A., Benech, C., and 72 others. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype. Am. J. Hum. Genet. 110: 215-227, 2023. [PubMed: 36586412] [Full Text: https://doi.org/10.1016/j.ajhg.2022.12.007]
Kojima, K. K., Jurka, J. Crypton transposons: identification of new diverse families and ancient domestication events. Mobile DNA 2: 12, 2011. [PubMed: 22011512] [Full Text: https://doi.org/10.1186/1759-8753-2-12]
Philips, A. K., Siren, A., Avela, K., Somer, M., Peippo, M., Ahvenainen, M., Doagu, F., Arvio, M., Kaariainen, H., Van Esch, H., Froyen, G., Haas, S. A., Hu, H., Kalscheuer, V. M., Jarvela, I. X-exome sequencing in Finnish families with intellectual disability--four novel mutations and two novel syndromic phenotypes. Orphanet J. Rare Dis. 9: 49, 2014. [PubMed: 24721225] [Full Text: https://doi.org/10.1186/1750-1172-9-49]
Scheer, M. P., van der Maarel, S., Kubart, S., Schulz, A., Wirth, J., Schweiger, S., Ropers, H.-H., Nothwang, H. G. DXS6673E encodes a predominantly nuclear protein, and its mouse ortholog DXHXS6673E is alternatively spliced in a developmental- and tissue-specific manner. Genomics 63: 123-132, 2000. [PubMed: 10662551] [Full Text: https://doi.org/10.1006/geno.1999.6027]
van der Maarel, S. M., Scholten, I. H. J. M., Huber, I., Philippe, C., Suijkerbuijk, R. F., Gilgenkrantz, S., Kere, J., Cremers, F. P. M., Ropers, H.-H. Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1. Hum. Molec. Genet. 5: 887-897, 1996. [PubMed: 8817323] [Full Text: https://doi.org/10.1093/hmg/5.7.887]