Alternative titles; symbols
HGNC Approved Gene Symbol: MBD5
Cytogenetic location: 2q23.1 Genomic coordinates (GRCh38) : 2:148,020,927-148,516,971 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q23.1 | Intellectual developmental disorder, autosomal dominant 1 | 156200 | Autosomal dominant | 3 |
MBD5 belongs to the methyl-CpG-binding domain (MBD) family and interacts with the Polycomb repressive deubiquitinase (PR-DUB) complex (see BAP1, 603089) (Baymaz et al., 2014).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned MBD5, which they designated KIAA1461. The deduced protein contains 1,498 amino acids. RT-PCR ELISA detected moderate expression in whole adult brain, but no expression was detected in peripheral tissues. Expression was moderate in cerebellum, weak in all other specific brain regions examined, and very weak in spinal cord and fetal brain.
Laget et al. (2010) reported that human MBD5 has 2 isoforms. The longer isoform (isoform-1) contains 1,448 amino acids and has an N-terminal MBD, a proline-rich segment, a proline-tryptophan-tryptophan-proline (PWWP) domain, and 2 nuclear localization signals (NLS). The shorter isoform (isoform-2) contains 851 amino acids and has an N-terminal MBD, a proline-rich segment, and an NLS. Western blot analysis confirmed that the 2 isoforms were expressed in cultured human cells. Quantitative RT-PCR revealed that Mbd5 isoform-1 was expressed in all mouse tissues tested, with lowest expression in embryo and highest expression in brain and testis. Expression of isoform-2 was relatively homogeneous in all mouse tissues tested, but it was high in oocytes. Expression of fluorescence-tagged MBD5 in NIH-3T3 mouse cells showed that both isoforms were nuclear proteins, with isoform-1 always found at chromocenters at methylated loci.
Wagenstaller et al. (2007) determined that the MBD5 gene contains 5 noncoding exons at its 5-prime end, followed by 10 coding exons.
By radiation hybrid analysis, Nagase et al. (2000) mapped the MBD5 gene to chromosome 2. Wagenstaller et al. (2007) stated that the MBD5 gene maps to chromosome 2q23.1.
By mutation analysis, Laget et al. (2010) showed that the MBD of MBD5 was required for its localization at chromocenters. Localization of MBD5 at chromocenters did not require the presence of methylated DNA, as MBD5 could bind DNA in cells that had lost methylation. In vitro analysis revealed that the MBD of MBD5 did not bind methylated DNA.
Using pull-down assays, Baymaz et al. (2014) showed that MBD5 and MBD6 (619458) interacted with human PR-DUB in a mutually exclusive manner. Mutation analysis revealed that interaction with the PR-DUB complex was through the highly homologous MBD of MBD5 and MBD6. Live-cell imaging showed that MBD6, but not MBD5, was recruited to sites of DNA damage, indicating that MBD5 and MBD6 had functional distinctions despite both binding to the PR-DUB complex.
Wagenstaller et al. (2007) identified a 200-kb deletion that removed 1 noncoding exon and the first 7 coding exons of the MBD5 gene (611472.0001) in a boy with intellectual developmental disorder (MRD1; 156200). The deletion was absent in parental DNA, and the remaining allele had a normal coding region. Wagenstaller et al. (2007) screened 415 DNAs from children with mental retardation and found 4 missense variants that were not present in 660 controls. No parental DNA was available to determine the origin of these mutations. Wagenstaller et al. (2007) stated that confirmation of the pathogenicity of these variants awaited screening of a panel enriched for epileptic seizures for which parental DNA was available.
From a large international multicenter collaboration, Talkowski et al. (2011) ascertained 65 patients with heterozygous deletion (63 cases) or translocation (2 cases) involving chromosome 2q23.1 (see 156200). The deletions ranged in size from 38 kb to greater than 19 Mb. The smallest region of overlap in all cases was confined to 1 gene, MBD5, and 14 (21.5%) of the 65 microdeletions and translocations were exclusively localized to MBD5, including several deletions that were restricted to noncoding regions and did not alter the protein sequence. The deletions or translocations were associated with haploinsufficiency of the MBD5 gene (22.5 to 55.4% of controls), as determined by mRNA expression analysis. Talkowski et al. (2011) also identified MBD5 deletions in approximately 0.18% of patients with autism spectrum disorders (see 156200) from 2 large cohorts (1,786 and 2,275 patients, respectively), whereas deletions at this locus were not found in 7,878 controls. Moreover, there was a significant association between a gly79-to-glu (G79E) missense variant in a highly conserved methyl-CpG-binding domain in 747 patients with autism spectrum disorder compared with 2,043 controls (odds ratio of 5.47, p = 0.012). Talkowski et al. (2011) noted that the MBD5 gene belongs to a family of genes involved in DNA methylation and/or chromatin remodeling, like MECP2 (300005), which is mutant or deleted in Rett syndrome (RTT; 312750), intellectual disabilities, and autism, providing further evidence that alterations of MBD5 may predispose to the risk of these neurodevelopmental disorders.
Carvill et al. (2013) identified a de novo heterozygous truncating mutation in the MBD5 gene (611472.0002) in a 20-year-old woman with severe mental retardation and epileptic encephalopathy.
In an 8-year-old Vietnamese boy with MRD1, Le and Ha (2021) identified a heterozygous splice site mutation in the MBD5 gene (611472.0004). The mutations was identified by next-generation sequencing and confirmed by Sanger sequencing.
In a boy with autosomal dominant intellectual developmental disorder (MRD1; 156200), Wagenstaller et al. (2007) identified a 200-kb deletion that removed 1 noncoding exon and the first 7 coding exons of the MBD5 gene. The deletion region was present in parental DNA but provided no information with regard to the origin of the deletion. In addition to mental retardation, the boy had a sandal gap between the first and second toe, but no facial dysmorphic features. He showed retarded motor development and had febrile seizures at age 8 months and seizures without fever starting at age 16 months. The boy was hypoactive, and social interactions were limited.
In a 20-year-old woman (T1898) with autosomal dominant intellectual developmental disorder (MRD1; 156200), Carvill et al. (2013) identified a de novo heterozygous frameshift mutation in the MBD5 gene (NM_018328.4), resulting in premature termination (Thr157GlnfsTer4). The patient had delayed development and onset of tonic-clonic seizures at age 6 months. She later developed absence seizures, focal dyscognitive seizures, focal seizures, and tonic seizures associated with multiple EEG abnormalities, consistent with epileptic encephalopathy. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In a 16-year-old boy with autosomal dominant intellectual developmental disorder (MRD1; 156200), Kleefstra et al. (2012) identified a de novo heterozygous 1-bp deletion at position 150 of the MBD5 gene, resulting in a frameshift with premature termination 31 amino acids downstream (Thr52HisfsTer31). The patient had short stature, macrocephaly, mild intellectual disability, seizures, and sleep and behavioral problems.
In an 8-year-old Vietnamese boy with autosomal dominant intellectual developmental disorder (MRD1; 156200), Le and Ha (2021) identified a heterozygous c.217-1G-C transition (c.217-1G-C, NM_001378120.1) in intron 6 of the MBD5 gene, predicted to result in a splicing abnormality. The mutation, which was identified by next-generation sequencing and confirmed by Sanger sequencing, disrupted the intron 6 splice acceptor site and was predicted to result in absent or disrupted protein.
Baymaz, H. I., Fournier, A., Laget, S., Ji, Z., Jansen, P. W. T. C., Smits, A. H., Ferry, L., Mensinga, A., Poser, I., Sharrocks, A., Defossez, P.-A., Vermeulen, M. MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domain. Proteomics 14: 2179-2189, 2014. [PubMed: 24634419] [Full Text: https://doi.org/10.1002/pmic.201400013]
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
Kleefstra, T., Kramer, J. M., Neveling, K., Willemsen, M. H., Koemans, T. S., Vissers, L. E. L. M., Wissink-Lindhout, W., Fenckova, M., van den Akker, W. M. R., Nadif Kasri, N., Nillesen, W. M., Prescott, T., and 10 others. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91: 73-82, 2012. [PubMed: 22726846] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.003]
Laget, S., Joulie, M., Le Masson, F., Sasai, N., Christians, E., Pradhan, S., Roberts, R. J., Defossez, P.-A. The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA. PLoS One 5: e11982, 2010. [PubMed: 20700456] [Full Text: https://doi.org/10.1371/journal.pone.0011982]
Le, T. N. U., Ha, T. M. T. MBD5-related intellectual disability in a Vietnamese child. Am. J. Med. Genet. 185A: 1321-1323, 2021. [PubMed: 33427406] [Full Text: https://doi.org/10.1002/ajmg.a.62077]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Talkowski, M. E., Mullegama, S. V., Rosenfeld, J. A., van Bon, B. W. M., Shen, Y., Repnikova, E. A., Gastier-Foster, J., Thrush, D. L., Kathiresan, S., Ruderfer, D. M., Chiang, C., Hanscom, C., and 23 others. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am. J. Hum. Genet. 89: 551-563, 2011. [PubMed: 21981781] [Full Text: https://doi.org/10.1016/j.ajhg.2011.09.011]
Wagenstaller, J., Spranger, S., Lorenz-Depiereux, B., Kazmierczak, B., Nathrath, M., Wahl, D., Heye, B., Glaser, D., Liebscher, V., Meitinger, T., Strom, T. M. Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am. J. Hum. Genet. 81: 768-779, 2007. [PubMed: 17847001] [Full Text: https://doi.org/10.1086/521274]