Online Mendelian Inheritance in Man (OMIM) (2024)

* 608668

ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 11; ZMYND11

Alternative titles; symbols

BS69

Other entities represented in this entry:

BONE MORPHOGENETIC PROTEIN RECEPTOR-ASSOCIATED MOLECULE 1, INCLUDED; BRAM1, INCLUDED

HGNC Approved Gene Symbol: ZMYND11

Cytogenetic location: 10p15.3 Genomic coordinates (GRCh38): 10:130,088-254,637 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
10p15.3	Intellectual developmental disorder, autosomal dominant 30	616083	Autosomal dominant	3

TEXT

Cloning and Expression

Using adenovirus E1A as bait in a yeast 2-hybrid screen of a 16-day whole mouse embryo cDNA library, followed by screening a human colon carcinoma cDNA library, Hateboer et al. (1995) cloned ZMYND11, which they called BS69. The deduced 562-amino acid protein had an apparent molecular mass of about 69 kD following in vitro transcription and translation. BS69 contains 2 N-terminal zinc finger motifs, followed by a nuclear localization signal and a C-terminal E1A-binding domain. Northern blot analysis detected a 4.7-kb transcript in all mouse tissues examined, with highest expression in kidney.

Using the transmembrane and cytoplasmic domains of mouse Bmpr1a (601299) as bait in a yeast 2-hybrid screen of a human placenta cDNA library, followed by screening a kidney cDNA library and 5-prime RACE, Kurozumi et al. (1998) cloned a splice variant of BS69 that they designated BRAM1. The deduced BRAM1 protein contains the C-terminal 186 amino acids of BS69 preceded by 12 amino acids unique to BRAM1. Northern blot analysis detected variable expression of 4.4-kb and 1.3-kb transcripts in all tissues examined. Following transfection in mouse fibroblasts, BRAM1 localized to the cytoplasm, whereas BS69 localized to the nucleus.

Masselink and Bernards (2000) noted that BS69 contains 3 motifs involved in transcription regulation: a PHD finger and bromodomain in its N-terminal half, and a MYND domain at its extreme C terminus. The MYND domain, which is also present in the BRAM1 variant, is a 2-zinc finger motif first identified in Drosophila Deaf1 (602635) and human MTG8 (133435).

Gene Function

By coimmunoprecipitation, Hateboer et al. (1995) confirmed direct interaction between BS69 and the 289-amino acid isoform of E1A (289R) following cotransfection in a human cell line; BS69 did not interact with the shorter 243R E1A isoform. Endogenous BS69 complexed with E1A in adenovirus-transformed human embryonic kidney cells. C-terminal deletion mutants of BS69 failed to interact with E1A. BS69 inhibited transactivation mediated by the 289R E1A protein, but not the 243R E1A protein. BS69 also suppressed E1A-stimulated transcription of retinoic acid receptor (see 180240) in COS cells.

Kurozumi et al. (1998) determined that BRAM1 interacts specifically with the kinase domain of BMPR1A. BS69 did not interact with BMPR1A, suggesting that the N terminus of BS69 interferes with this interaction. Further investigation indicated that BRAM1 also interacts with TAB1 (602615). Kurozumi et al. (1998) hypothesized that a ternary complex of MBPR1A, TAB1, and BRAM1 may be involved in BMP-TAB1-TAK1 (601426) signaling.

Masselink and Bernards (2000) determined that full transcriptional repression by BS69 requires the MYND domain. BS69 and BRAM1 interacted with NCOR (600849) through the MYND domain, but BRAM1 was unable to repress transcription, indicating that NCOR interaction is necessary but not sufficient for BS69 repression. Expression of E1A inhibited repression mediated by BS69.

Ansieau and Leutz (2002) showed that the MYND domain of BS69 interacts with a conserved PxLxP motif in E1A, the Epstein-Barr virus oncoprotein EBNA2, and a MYC (190080)-related cellular protein, MGA (616061). The viral proteins competed with MGA for BS69 binding in a PxLxP-dependent fashion.

Wen et al. (2014) showed that ZMYND11 specifically recognizes H3 with trimethylated lysine-36 (H3K36me3) on H3.3 (H3.3K36me3) (see 601128) and regulates RNA polymerase II (see 180660) elongation. Chromatin immunoprecipitation followed by sequencing showed a genomewide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy required the predeposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; low expression levels of ZMYND11 in breast cancer patients correlated with worse prognosis. Overexpression of ZMYND11 consistently suppressed cancer cell growth in vitro and tumor formation in mice. Wen et al. (2014) concluded that this study (see also BIOCHEMICAL FEATURES) identified ZMYND11 as an H3.3-specific reader of H3K36me3 that links histone variant-mediated transcription elongation control to tumor suppression.

Biochemical Features

Wen et al. (2014) solved the crystal structure of the tandem bromo-PWWP domain of ZMYND11 in its free state and in complex with H3.3 with trimethylated lysine-36 (H3.3K36me3) peptide at 1.95- and 2.0-angstrom resolution, respectively. In addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific ser31 residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Wen et al. (2014) also solved the structure of ZMYND11 bromo-PWWP-H3.1K36me3 (see 602810) complex at 2.3-angstrom resolution for comparison. These studies indicated that the H3.3-specific ser31 residue is indispensable for ZMYND11-H3K36me3 interaction and strongly supported a role of ZMYND11 as an H3.3-specific reader of H3K36me3.

Mapping

By FISH, Masselink and Bernards (2000) mapped the ZMYND11 gene to chromosome 10p14.

Molecular Genetics

In a large study of copy number variation (CNV) in neurodevelopmental disease and genes potentially sensitive to dosage imbalance, Coe et al. (2014) identified 6 truncating mutations in ZMYND11 (e.g., 608668.0001-608668.0005) in 7 individuals from 6 families with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083). One affected individual had inherited the mutation from his more mildly affected father. In 2 cases, those of a 9-year-old female and a 17-year-old female, the mutations occurred as de novo events. In the remaining patients, inheritance could not be determined. Coe et al. (2014) created an expanded copy number variant (CNV) morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. They then resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Among these was ZMYND11, haploinsufficiency for which was associated with mild intellectual disability, neuropsychiatric behavioral features, and subtle facial dysmorphism.

In 16 patients with MRD30, Yates et al. (2020) reported heterozygous mutations in the ZMYND11 gene (see, e.g., 608668.0006-608668.0009). The patients were ascertained through international collaborative efforts after the mutations were identified through exome sequencing. The mutations were confirmed by Sanger sequencing; none were present in the gnomAD database. Eight occurred de novo, 1 was inherited by 3 sibs from their mildly affected mother, 1 was paternally inherited, and 3 were of unknown inheritance. The mutations occurred throughout the gene. Ten variants were predicted to result in protein truncation, 2 were missense, and 1 affected a splice site. Functional studies of the variants and studies of patient cells were not performed. The authors hypothesized a loss of function and haploinsufficiency of ZMYND11 as the most likely pathogenetic mechanism, although other mechanisms could not be ruled out.

In a review of 43 ZMYND11 putative pathogenic variants in patients with MRD30, Oates et al. (2021) noted that different types of mutations had been identified, including missense and those resulting in premature termination. The vast majority of mutations occurred de novo, but there were several instances of parental transmission with reduced penetrance and variable expressivity. There were no genotype/phenotype correlations. Functional studies of the variants and studies of patient cells were not performed.

ALLELIC VARIANTS 9 Selected Examples):

.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, 3-BP DEL
SNP: rs606231266, ClinVar: RCV000144895

In a 9-year-old female (Adelaide20124) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Coe et al. (2014) identified a de novo heterozygous 3-bp deletion in the ZMYND11 gene (g.298360_298362del), resulting in deletion of gln587 (Q587). Functional studies of the variant were not performed. She had global developmental delay and dysmorphic craniofacial features that included brachycephaly, upslanting palpebral fissures, a wide mouth, bowed upper lip, and diastema.

.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, 1-BP DUP
SNP: rs606231267, ClinVar: RCV000144896

In a 17-year-old female (DNA-017151) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Coe et al. (2014) identified a heterozygous duplication in the ZMYND11 gene (g.255918dup) leading to a thr70-to-asn (T70N) substitution and frameshift that resulted in a termination codon 12 amino acids later (Thr70AsnfsTer12). Functional studies of the variant were not performed. At the age of 8 years full-scale IQ was 73, verbal IQ 80, and nonverbal IQ 68, but perceptual organization IQ was 62. Difficulties in social and emotional development and behavioral problems suggested autism spectrum disorder, but symptoms were not sufficient to make a diagnosis of ASD. This mutation occurred as a de novo event. Facial dysmorphisms included small ears with overfolded upper helices and prominent antihelices, mild ptosis, and wide mouth. She also had joint laxity, clinodactyly, hallux valgus, and long second and fourth toes. CT scan was normal at 21 months of age.

.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, GLN326TER
SNP: rs672601340, ClinVar: RCV000144897

In a 41-year-old man (DNA04-02424) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Coe et al. (2014) identified a heterozygous C-to-T transition in the ZMYND11 gene (g.292731C-T) resulting in a gln326-to-ter (Q326X) substitution. Functional studies of the variant were not performed. The patient also had rapidly cycling bipolar disorder, borderline personality disorder, and pervasive developmental disorder, with psychosis and substance abuse. Other than hypertelorism and cubiti valgi, physical examination was normal. Inheritance of this mutation was undetermined.

.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, 2-BP DEL
SNP: rs606231268, ClinVar: RCV000144898

In a 32-year-old man (DNA05-04370) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Coe et al. (2014) identified a heterozygous 2-bp deletion in the ZMYND11 gene (g.294294_294295del) resulting in a glu416-to-ser substitution followed by frameshift and premature termination after 5 amino acids (Glu416SerfsTer5). Functional studies of the variant were not performed. The patient had short stature, microcephaly, severe intellectual disability, and speech and motor delays. The patient also had a long philtrum, asymmetric skull, deep-set eyes, hypertelorism, and overfolded upper helix. Brain CT scan showed mild atrophy. Origin of the mutation was not determined.

.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, 1-BP DEL
SNP: rs672601341, ClinVar: RCV000144899

In a 25-year-old man (DNA-013587) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083) and in his more mildly affected father, Coe et al. (2014) detected heterozygosity for a 1-bp deletion in the ZMYND11 gene (g.283569del) that resulted in a met187-to-ile substitution followed by frameshift and premature termination of the protein (Met187IlefsTer19). Functional studies of the variant were not performed. The proband had an IQ of 63 at age 9 years and 66 at age 18 years but of 55 at age 25 years. He had significant problems with low frustration tolerance and aggressive and provocative behavior, requiring treatment with risperidone. Dysmorphic features included synophrys, ptosis, and hypertelorism. The father of the proband had developmental delay but could read, write, calculate, and obtain a driving license. He had behavioral problems in childhood that included aggression and mood swings.

.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, TYR210TER
ClinVar: RCV002282711

In a 5-year-old girl (P3) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Yates et al. (2020) identified a de novo heterozygous c.630C-G transversion (c.630C-G, NM_006624.5) in the ZMYND11 gene, resulting in a tyr210-to-ter (Y210X) substitution. The mutation, which was found by exome 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 patient had seizures and dysmorphic features.

.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, TRP363TER
ClinVar: RCV002282712

In an 8-year-old boy (P5) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Yates et al. (2020) identified a de novo heterozygous c.1089G-A transition (c.1089G-A, NM_006624.5) in the ZMYND11 gene, resulting in a trp363-to-ter (W363X) substitution. The mutation, which was found by exome 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 patient had dysmorphic features; he did not have seizures.

.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, 1-BP DUP, NT1572
ClinVar: RCV002282713

In a 2.7-year-old girl (P10) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Yates et al. (2020) identified a de novo heterozygous 1-bp duplication (c.1572dup, NM_006624.5) in the ZMYND11 gene, predicted to result in a frameshift and premature termination (Asp525GlyfsTer5). The mutation, which was found by exome 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 patient had dysmorphic features; she did not have seizures.

.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES

ZMYND11, GLN586TER
ClinVar: RCV002282714

In 3 sibs (P12, P13, and P14) with autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30; 616083), Yates et al. (2020) identified a heterozygous c.1756C-T transition (c.1756C-T, NM_006624.5) in the ZMYND11 gene, resulting in a gln586-to-ter (Q586X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the mildly affected mother (P15). It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patients were able to attend special schools; one of the sibs had seizures and the mother had a history of childhood seizures.

REFERENCES

Ansieau, S., Leutz, A. The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif. J. Biol. Chem. 277: 4906-4910, 2002. [PubMed: 11733528] [Full Text: https://doi.org/10.1074/jbc.M110078200]
Coe, B. P., Witherspoon, K., Rosenfeld, J. A., van Bon, B. W. M., Vulto-van Silfhout, A. T., Bosco, P., Friend, K. L., Baker, C., Buono, S., Vissers, L. E. L. M., Schuurs-Hoeijmakers, J. H., Hoischen, A., and 26 others. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature Genet. 46: 1063-1071, 2014. [PubMed: 25217958] [Full Text: https://doi.org/10.1038/ng.3092]
Hateboer, G., Gennissen, A., Ramos, Y. F. M., Kerkhoven, R. M., Sonntag-Buck, V., Stunnenberg, H. G., Bernards, R. BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation. EMBO J. 14: 3159-3169, 1995. [PubMed: 7621829] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb07318.x]
Kurozumi, K., Nish*ta, M., Yamaguchi, K., Fujita, T., Ueno, N., Shibuya, H. BRAM1, a BMP receptor-associated molecule involved in BMP signalling. Genes Cells 3: 257-264, 1998. [PubMed: 9663660] [Full Text: https://doi.org/10.1046/j.1365-2443.1998.00186.x]
Masselink, H., Bernards, R. The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoR. Oncogene 19: 1538-1546, 2000. [PubMed: 10734313] [Full Text: https://doi.org/10.1038/sj.onc.1203421]
Oates, S., Absoud, M., Goyal, S., Bayley, S., Baulcomb, J., Sims, A., Riddett, A., Allis, K., Brasch-Andersen, C., Balasubramanian, M., Bai, R., Callewaert, B., and 23 others. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder. Clin. Genet. 100: 412-429, 2021. [PubMed: 34216016] [Full Text: https://doi.org/10.1111/cge.14023]
Wen, H., Li, Y., Xi, Y., Jiang, S., Stratton, S., Peng, D., Tanaka, K., Ren, Y., Xia, Z., Wu, J., Li, B., Barton, M. C., Li, W., Li, H., Shi, X. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 508: 263-268, 2014. [PubMed: 24590075] [Full Text: https://doi.org/10.1038/nature13045]
Yates, T. M., Drucker, M., Barnicoat, A., Low, K., Gerkes, E. H., Fry, A. E., Parker, M. J., O'Driscoll, M., Charles, P., Cox, H., Marey, I., Keren, B., and 10 others. ZMYND11-related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum. Hum. Mutat. 41: 1042-1050, 2020. [PubMed: 32097528] [Full Text: https://doi.org/10.1002/humu.24001]

Contributors:

Cassandra L. Kniffin - updated : 09/01/2022
Ada Hamosh - updated : 11/6/2014
Ada Hamosh - updated : 6/3/2014

Creation Date:

Patricia A. Hartz : 5/19/2004

Edit History:

alopez : 09/08/2022
ckniffin : 09/01/2022
alopez : 04/12/2022
joanna : 11/06/2014
alopez : 11/6/2014
mgross : 10/24/2014
alopez : 6/3/2014
carol : 5/19/2004
mgross : 5/19/2004
mgross : 5/19/2004