Alternative titles; symbols
HGNC Approved Gene Symbol: MBD4
Cytogenetic location: 3q21.3 Genomic coordinates (GRCh38) : 3:129,430,947-129,439,948 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.3 | {Uveal melanoma, susceptibility to, 1} | 606660 | Autosomal dominant | 3 |
| Tumor predisposition syndrome 2 | 619975 | Autosomal recessive | 3 |
The MBD4 gene encodes a methylcytosine-binding domain (MBD)-containing base excision repair (BER) glycosylase that prevents mutability at CpG sites by removing thymine (T) and uracil (U) from G:T and G:U mismatches that arise from spontaneous deamination of 5-methylcytosine (5mC) and cytosine (C), respectively. MBD4 is also a binding partner of the mismatch repair (MMR) protein MLH1 (120436) and modulates the levels of core MMR proteins. Thus, MBD4 plays a role in maintaining genetic integrity (summary by Tricarico et al., 2015 and Busque and Godley, 2018).
DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. MBD4 specifically binds methylated DNA, colocalizes with methylated sequences, and is likely to mediate the effects of DNA methylation in mammalian cells (Hendrich and Bird, 1998).
The MECP2 (300005) and MBD1 (156535) proteins bind specifically to methylated DNA via a methyl-CpG-binding domain (MBD). By searching an EST database for proteins containing an MBD-like motif, Hendrich and Bird (1998) identified human and mouse cDNAs encoding the 3 novel proteins MBD2 (603547), MBD3 (603573), and MBD4. The predicted 580-amino acid human MBD4 protein (GenBank AF072250) is 66% identical to mouse Mbd4. The authors found evidence of alternatively spliced human and mouse MBD4 transcripts; one form encodes a truncated human MBD4 protein lacking the C-terminal 42 amino acids.
Using reverse RNA dot blot analysis, Galetzka et al. (2007) found that expression of MBD2, MBD4, DNMT1 (126375), and DNMT3A (602769) was tightly linked during the development of human fetal gonads. They suggested that concomitant upregulation of these genes is associated with prenatal remethylation in the male and female germlines.
Hendrich and Bird (1998) found that both MBD2 and MBD4 specifically bound methylated DNA in vitro and colocalized with methylated sequences in vivo. They concluded that MBD2 and MBD4 are likely to be mediators of the effects of DNA methylation in mammalian cells.
Hendrich et al. (1999) showed that MBD4 contains a methyl-CpG-binding domain that can efficiently remove thymine or uracil from mismatched CpG sites in vitro. Furthermore, the methyl-CpG-binding domain of MBD4 binds preferentially to 5-methylcytosine CpG-TpG mismatches--the primary product of deamination at methyl-CpG. The combined specificities of binding and catalysis indicated that this enzyme may function to minimize mutation at methyl-CpG.
The DNA mismatch repair (MMR) is a specialized system, highly conserved throughout evolution, involved in the maintenance of genomic integrity. To identify novel human genes that may function in MMR, Bellacosa et al. (1999) used the yeast interaction trap. Using the MMR protein MLH1 (120436) as bait, they cloned MBD4, which they called MED1. The MED1 protein formed a complex with MLH1, bound to methyl-CpG-containing DNA, exhibited homology to bacterial DNA repair glycosylases/lyases, and displayed endonuclease activity. Transfection of a MED1 mutant lacking the MBD was associated with microsatellite instability. These findings suggested that MED1 is a human DNA repair protein that may be involved in MMR and, as such, may be a candidate eukaryotic homolog of the bacterial MMR endonuclease, MutH. In addition, these results suggested that cytosine methylation may play a role in human DNA repair.
Cortellino et al. (2003) found that, unlike wildtype and Med1 +/- mouse embryonic fibroblasts, Med1 -/- cells failed to undergo G2/M cell cycle arrest and apoptosis upon treatment with a methylating agent or platinum compounds. Similar to cells defective in mismatch repair, the resistance of Med1 -/- fibroblasts to the methylating agent was due to a tolerance mechanism because DNA damage accumulated but did not elicit checkpoint activation. The steady state amounts of several mismatch repair proteins were reduced in Med1 -/- fibroblasts compared with wildtype or heterozygous fibroblasts. Cortellino et al. (2003) concluded that MED1 is associated with the integrity of the mismatch repair system and that MED1 defects may impair cell cycle arrest and apoptosis induced by DNA damage.
By genomic sequence analysis, Hendrich et al. (1999) determined that the murine Mbd4 gene contains 7 exons spanning 11 kb. The MBD is encoded by exons 2 and 3. They found that the human MBD4 gene has a similar structure, except that it contains a 77-kb intron inserted into the sequence corresponding to mouse exon 4, resulting in exons 4A and 4B in human.
Using PCR on a hybrid panel and FISH, Hendrich et al. (1999) mapped the MBD4 gene to chromosome 3q. They mapped the mouse gene to chromosome 6. Riccio et al. (1999) mapped the MBD4 gene to chromosome 3q21-q22 by FISH.
Somatic Mutations
Riccio et al. (1999) detected somatic MBD4 mutations in 14 of 56 (25%) of primary microsatellite-instability (MSI) tumors, 11 of 42 (26.2%) of colorectal carcinomas, 2 of 9 (22.2%) of endometrial carcinomas, and 1 of 5 (20%) of pancreatic tumors. No microsatellite-stable (MSS) tumors contained MBD4 mutations at coding polyadenine tracts, suggesting that these mutations are restricted to MSI tumors. All mutations identified in MBD4 targeted the A10 tract, the polyadenine tract at codons 310 to 313, indicating that this is a mutation hotspot in MBD4. Four of 6 colorectal tumors examined using LOH analysis had evidence of biallelic inactivation of MBD4. Thus, MBD4 meets 4 of 5 criteria of a bona fide MIS target gene (Boland et al., 1998).
Tumor Predisposition Syndrome 2
In 2 sisters and an unrelated man with tumor predisposition syndrome-2 (TPDS2; 619975) manifest as acute myeloid leukemia (AML) and variable colorectal polyposis, Sanders et al. (2018) identified homozygous or compound heterozygous germline mutations in the MBD4 gene (603574.0001-603574.0003). The mutations, which were found by whole-genome or whole-exome sequencing and confirmed by Sanger sequencing, encoded an in-frame deletion, a frameshift, and a splice site defect, suggesting a loss-of-function effect. In vitro functional expression studies of one of the mutations (His567del; 603574.0001) showed that it resulted in a complete loss of MBD4 catalytic activity. The splice site mutation (603574.0002) was demonstrated to cause skipping of exon 7, predicted to result in disruption of the catalytic domain. Tumor tissue from the patients showed a 33-fold higher level of mutations than in sporadic AML, with over 95% of the mutations being C-to-T transitions that occurred within a CG dinucleotide, suggesting a failure to detect a deaminated m5C base. In addition to the high C-T transition mutational burden, all 3 leukemia cases shared acquired somatic mutations in other genes, such as DNMT3A (602769) which is a key driver gene for both clonal hematopoiesis and AML. Analysis of a large Cancer Genome Atlas database of 10,683 individuals with various types of cancer identified 9 patients (0.8%) with heterozygous germline mutations in the MBD4 gene, including the splice site variant (603574.0002) that was found in compound heterozygous state in the sisters with AML. All of the mutations identified in the 9 patients from the cancer database were nonsense or splice site, predicted to result in a loss of function. Tumor types in these individuals included glioblastoma multiforme, ovarian cancer, endometrial cancer, thymoma, uveal melanoma, stomach adenocarcinoma, and cholangiocarcinoma. Tumor tissue from 2 of these patients, uveal melanoma (TCGA-UVM-1) and glioblastome multiforme (TCGA-GBM-1), showed loss of heterozygosity at the MBD4 allele. These 2 cases and the 3 AML cases showed an elevated overall mutation rate with strong enrichment for CG-TG mutations, whereas the cancers that retained a wildtype allele did not display a prominent CG-TG signature. These findings suggested that both MBD4 alleles must be inactivated to inhibit repair activity, consistent with other BER (base excision repair)-associated cancer syndromes. The authors concluded that germline MBD4 deficiency results in methylation damage that enhances cancer susceptibility and predisposes to AML.
In a 42-year-old Japanese woman with TPDS2 manifest as colorectal tubular adenocarcinoma, Tanakaya et al. (2019) identified a germline heterozygous nonsense mutation in the MBD4 gene (Q73X; 603574.0004). The mutation, which was found by panel sequencing combined with whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (8.237 x 10(-6)) in the ExAC database and at a low frequency (0.0002) in a Japanese control database. Immunohistochemical analysis of patient tumor tissue showed loss of MBD4 expression, whereas it was clearly expressed in normal epithelial cells. Sanger sequencing confirmed that the tumor tissue was homozygous for the Q73X mutation, indicating that inactivation of the wildtype MBD4 allele had occurred in the tumor tissue. Copy number analysis showed LOH around the MBD4 locus. Cancer tissue demonstrated multiple C-to-T transitions that occurred preferentially at CpG sites, consistent with the role of MBD4 in the maintenance of genomic stability at CpG sites. The patient had no family history of the colorectal cancer, although her brother died at age 36 years of hepatocellular carcinoma associate with chronic hepatitis B infection; no biologic material was available for study from the brother.
In 5 patients from 4 unrelated families with TPDS2, Palles et al. (2022) identified germline homozygous or compound heterozygous loss-of-function frameshift or nonsense mutations in the MBD4 gene (603574.0003; 603574.0005; 603574.0006). The mutations, which were found by whole-exome, whole-genome, or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the 2 families from whom DNA was available for study. None were found in the homozygous state in the gnomAD database. Colorectal adenoma tumor tissue derived from 2 patients (family D and patient WEHI-AML-2, previously reported by Sanders et al., 2018) showed a significantly increased somatic mutation burden compared to sporadic adenomas, and most of the mutations in the adenomas from the TPDS2 patients were CpG-TpG transitions. Potential driver genes that were mutated in the tumor tissue included APC (611731) and AMER1 (300647). Moreover, most of these mutated sites identified were methylated in normal colon tissue. The findings were fully consistent with a failure to mutant MBD4 to repair G-T mismatches that resulted from spontaneous deamination of 5mC.
Melanoma, Uveal, Susceptibility to, 1
MBD4 is thought to act as a tumor suppressor gene, following the Knudson 2-hit model of cancer development with somatic loss of the wildtype allele in tumor tissue driving tumor progression in individuals who have heterozygous germline MBD4 mutations. The LOH of MBD4 is often represented by somatic monosomy 3 in uveal melanoma tumors (summary by Derrien et al., 2021).
Rodrigues et al. (2018) reported 2 unrelated patients (UVM_1C and UVM_1) with uveal melanoma whose tumors showed a hypermutated CpG-TpG signature. Both individuals carried a heterozygous germline loss-of-function (splice site or frameshift) mutation in the MBD4 gene (see, e.g., 603574.0002), and analysis of all the tumors showed monosomy 3 with somatic loss of the second MBD4 allele. Tumor tissue from both patients also showed a somatic mutation in the tumor suppressor gene BAP1 (603089). Patient UVM_1 had relatively early onset of the cancer before age 50 years. Of note, patient UVM_1C was a woman diagnosed with metastatic uveal melanoma at age 76. She showed a dramatic positive response to treatment with pembrolizumab, a 'programmed cell death protein 1 inhibitor.' None of the patients had a family history of cancer; only patient UVM_1C had a history of breast ductal carcinoma in situ. The findings indicated that heterozygous germline mutations in the MBD4 gene may not be sufficient to initiate tumorigenesis, but may play a significant role in tumor progression if somatic mutations are acquired.
In a 65-year-old woman with uveal melanoma-2 with later metastases, Johansson et al. (2019) identified a germline heterozygous L563X mutation (603574.0005) in the MBD4 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of tumor tissue showed a heavy mutation burden with mostly (74%) CpG-CpT transitions. There was showed somatic monosomy 3 with loss of heterozygosity at the MBD4 allele, as well as several other somatic changes, including gain of chromosome 8, a mutation in the BAP1 gene (603089), and monosomy 13. Despite treatment with a checkpoint inhibitor, which stabilized the disease and prolonged her survival, she died 2 years later. Johansson et al. (2019) concluded that heterozygous mutation in the MBD4 gene causes a predisposition to the development of uveal melanoma.
Through targeted sequencing analysis of large cohorts of patients with uveal melanoma, Derrien et al. (2021) identified heterozygous germline loss-of-function mutations in the MBD4 gene (see, e.g., 603574.0002, 603574.0007 and 603574.0008). Eleven unrelated patients were identified; none had familial or bilateral uveal melanoma, and none had other MBD4-related tumors or malignancies. A variety of mutation types was identified, but most pathogenic ones were predicted or demonstrated to result in a loss of function. Tumor tissue, when available, showed a high tumor mutation burden characterized mainly by a CpG-TpG mutational pattern and somatic loss of the wildtype MBD4 allele. The identification of MBD4 mutations in these cohorts indicated that the prevalence of MBD4 germline mutations in UVM1 is about 0.7%. The authors concluded that the presence of heterozygous germline MBD4 mutations strongly predisposes to uveal melanoma (relative risk of 9.15) compared to the general population.
Millar et al. (2002) generated Mbd4 knockout mice by targeted disruption. Mbd4 -/- mice had a 3-fold increase in the frequency of C-to-T transitions at CpG sites. When bred onto the Apc(Min/+) background (see 611731), Mbd4 -/- mice showed accelerated tumor formation with CpG-to-TpG mutations in the Apc gene. Thus, Millar et al. (2002) concluded that MBD4 suppresses CpG mutability and tumorigenesis in vivo.
To clarify the role of Mbd4 in DNA repair in vivo and to examine the impact of Mbd4 inactivation on gastrointestinal tumorigenesis, Wong et al. (2002) introduced a null mutation into the mouse Mbd4 gene by gene targeting. Heterozygous and homozygous Mbd4 mutant mice developed normally and did not show increased cancer susceptibility or reduced survival. Although Mbd4 inactivation did not increase MSI in the mouse genome, it did result in a 2- to 3-fold increase in C-to-T transition mutations at CpG sequences in splenocytes and epithelial cells of the small intestinal mucosa. The combination of Mbd4 deficiency with a germline mutation in the Apc gene increased the tumor number in the gastrointestinal tract and accelerated tumor progression. The change in the gastrointestinal cancer phenotype was associated with an increase in somatic C-to-T mutations at CpG sites within the coding region of the wildtype Apc allele. These studies indicated that although inactivation of Mbd4 does not by itself cause cancer predisposition in mice, it can alter the mutation spectrum in cancer cells and modify the cancer predisposition phenotype.
The article by Kim et al. (2009) on DNA demethylation in hormone-induced transcriptional derepression was retracted.
In a man (EMC-AML-1) with tumor predisposition syndrome-2 (TPDS2; 619975) who was diagnosed with acute myelogenous leukemia (AML) at age 33 years, Sanders et al. (2018) identified a germline homozygous in-frame 3-bp deletion (c.1699_1701delATG, NM_003925.2) in the MBD4 gene, resulting in the deletion of residue His567 (H567del) in the glycosylase domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that deletion of His567 resulted in a complete loss of MBD4 catalytic activity. Despite 2 hematopoietic stem cell transplants, the AML was refractory to treatment and recurred, resulting in death several years after initial diagnosis. The patient also had a prior history of multiple colonic polyps requiring hemicolectomy.
Note: The protein change resulting from the c.1561-1G-T mutation based on NM_003925.2 reported by Palles et al. (2022) and Derrien et al. (2021) differ: Asp521Gly6fsTer4 and Asp521ProfsTer4, respectively.
Tumor Predisposition Syndrome 2
In 2 sisters (WEHI-AML-1 and WEHI-AML-2) with tumor predisposition syndrome-2 (TPDS2; 619975) manifest as acute myelogenous leukemia (AML), Sanders et al. (2018) identified compound heterozygous mutations in the MBD4 gene: a G-to-T transversion in intron 7 (c.1562-1G-T, NM_003925.2), resulting in a splicing defect that disrupts the glycosylase domain, and a 1-bp duplication (c.939dupA; 603574.0003), resulting in a frameshift and premature termination (Val314ArgfsTer13). The mutations were found by whole-genome sequencing and exome capture analysis and confirmed by Sanger sequencing. Both mutations were predicted to result in a loss-of-function. One sister (WEHI-AML-1) developed AML at age 31 years and received a hematopoietic stem cell transplant (HSCT) from her sister (WEHI-AML-2), who had not yet developed the disease. WEHI-AML-1 relapsed and died about 12 months after diagnosis. WEHI-AML-2 developed AML at age 34 years. She underwent HSCT and achieved remission. Patient WEHI-AML-2 also had a history of colorectal polyps. By mining of a large cancer database, Sanders et al. (2018) identified a heterozygous germline c.1562-1G-T mutation in a patient with serous ovarian cancer (TCGA-OV-1) and in a patient with uveal melanoma (TCGA-UVM-1). In the patient with uveal melanoma, the splice site mutation was accompanied by somatic loss of the wildtype MBD4 allele in the tumor, suggesting that biallelic loss of MBD4 is required to inhibit the DNA repair activity.
Palles et al. (2022) found that colorectal adenomas from patient WEHI-AML-2, reported by Sanders et al. (2018), contained a significantly increased somatic mutation burden compared to 9 sporadic adenomas (1.8), and most of the mutations in the adenomas from the TPDS2 patient were CG-TG transitions. Potential driver genes that were mutated in the tumor tissue included APC (611731) and AMER1 (300647). Palles et al. (2022) stated that the c.1562-1G-T transversion resulted in a splicing defect, a frameshift, and premature termination (Asp521GlyfsTer4).
Melanoma, Uveal, Susceptibility to, 1
Rodrigues et al. (2018) reported a patient (UVM_1) who developed uveal melanoma (UVM1; 606660) at 41 years of age. She was found to carry a heterozygous germline c.1562-1G-T mutation in the MBD4 gene. Tumor tissue from the patient showed hypermutation with a high level of CpG-TpG somatic variants, a somatic mutation in the BAP1 gene (603089), and somatic monosomy 3 with loss of the wildtype allele at the MBD4 locus. The patient had no family history of cancer.
Derrien et al. (2021) identified a germline heterozygous c.1562-1G-T mutation in the MBD4 gene in 3 unrelated individuals with UMV1 (patients UM49, UM1088, and UMT45). The authors stated that the variant resulted in an Asp521ProfsTer4 frameshift. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. Tumor tissue available from 1 patient showed somatic loss of the wildtype MBD4 allele and a high tumor mutation burden. The variant was found in 10 of 251,472 alleles (3.98 x 10(-5)) in the gnomAD database (v.2.1.1).
Note: The protein change resulting from the c.939dup mutation differed in the reports of Sanders et al. (2018) and Palles et al. (2022): Val314ArgfsTer13, NM_003925 and Glu314ArgfsTer13, NM_003925.2, respectively.
For discussion of the 1-bp duplication (c.939dup, NM_003925) in the MBD4 gene, resulting in a frameshift and premature termination (Val314ArgfsTer13), that was found in compound heterozygous state in 2 sisters with tumor predisposition syndrome-2 (TPDS2; 619975) by Sanders et al. (2018), see 603574.0002.
In 2 sibs (family CRDFF-336) and an unrelated man (family CRDFF-292) with TPDS2, Palles et al. (2022) identified a homozygous germline c.939dup mutation (NM_003925.2) in the MBD4 gene, resulting in a frameshift (Glu314ArgfsTer13). The mutation, which was found by whole-exome, whole-genome, or targeted sequencing and confirmed by Sanger sequencing, was present only in the heterozygous state in the gnomAD database (6.53 x 10(-4)). Another woman with the disorder (family DB1) was found to be compound heterozygous for c.939dup and a c.1688T-A transversion, resulting in a leu563-to-ter (L563X; 603574.0005) substitution. The patients had onset of various types of tumors as young adults, including multiple colorectal polyps and adenomas, ovarian granulosa cell tumor, uveal melanoma, meningiomas, and schwannomas. The patient from family CRDFF-292 had a deceased brother with colorectal carcinoma and leukemia, but DNA from this individual was not available. The patient from family DB1 had a deceased affected sister with colorectal adenomas, uveal melanomas, and AML; DNA was not available from this individual. The parents of the sibs in family CRDFF-336 each carried the mutation in heterozygosity, consistent with autosomal recessive inheritance.
In a 42-year-old Japanese woman with tumor predisposition syndrome-2 (TPDS2; 619975) manifest as colorectal tubular adenocarcinoma, Tanakaya et al. (2019) identified a germline heterozygous c.217C-T transition in exon 2 of the MBD4 gene, resulting in a gln73-to-ter (Q73X) substitution. The mutation, which was found by panel sequencing combined with whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (8.237 x 10(-6)) in the ExAC database and at a low frequency (0.0002) in a Japanese control database. Immunohistochemical analysis showed loss of MBD4 expression in patient tumor tissue whereas there was clear expression in normal epithelial cells. Sanger sequencing confirmed that the tumor tissue was homozygous for the Q73X mutation, indicating that inactivation of the wildtype MBD4 allele had occurred in the tumor tissue. Copy number analysis showed LOH around the MBD4 locus. Cancer tissue demonstrated multiple C-to-T transitions that occurred preferentially at CpG sites, consistent with the role of MBD4 in the maintenance of genomic stability at CpG sites. The patient had no family history of colorectal cancer, although her brother died at age 36 years of hepatocellular carcinoma associated with chronic hepatitis B infection; no biologic material was available for study from the brother.
Tumor Predisposition Syndrome 2
For discussion of the c.1688T-A transversion in the MBD4 gene, resulting in a leu563-to-ter (L563X) substitution, that was found in compound heterozygous state in a patient with tumor predisposition syndrome-2 (TPDS2; 619975) by Palles et al. (2022), see 603574.0003.
Melanoma, Uveal, Susceptibility to, 1
In a 65-year-old woman with uveal melanoma-1 (UVM1; 606660), Johansson et al. (2019) identified a germline heterozygous L563X mutation in the MBD4 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of tumor tissue showed a heavy mutation burden with mostly (74%) CpG-to-CpT transitions. There showed somatic monosomy 3 with loss of heterozygosity at the MBD4 allele, as well as several other somatic changes, including gain of chromosome 8, a mutation in the BAP1 gene (603089), and monosomy 13. Despite treatment with a checkpoint inhibitor, which stabilized the disease and prolonged her survival, she died 2 years later. Johansson et al. (2019) concluded that heterozygous mutation in the MBD4 gene causes a predisposition specifically to the development of uveal melanoma.
In a man (family D) with tumor predisposition syndrome-2 (TPDS2; 619975), Palles et al. (2022) identified a homozygous 4-bp deletion (c.612_615del) in the MBD4 gene, resulting in a frameshift and premature termination (Ser205ThrfsTer9). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present at a low frequency (4.0 x 10(-5)) in only heterozygous state in the gnomAD database. The patient had multiple colorectal adenomas and myelodysplastic syndrome that evolved to AML. Colorectal adenomas from the patient showed a significantly increased somatic mutation burden (11.1) compared to 9 sporadic adenomas (1.8), and most of the mutations in the adenomas from the TPDS2 patient were CG-TG transitions. Other potential driver genes that were mutated in the tumor tissue included APC (611731) and AMER1 (300647). Western blot analysis of lymphoblastoid cells from the patient showed absence of the MBD4 protein, consistent with a complete loss of function.
In 2 unrelated patients (UM75 and UM1033) with uveal melanoma-1 (UVM1; 606660), Derrien et al. (2021) identified a germline heterozygous c.1706G-A transition in the MBD4 gene, resulting in a trp569-to-ter (W569X) substitution. The variant was found in 2 of 282,518 alleles (7.08 x 10(-6)) in the gnomAD database (v.2.1.1). In vitro functional expression studies showed that the mutation abolished glycosylase activity, consistent with a loss of function. Tumor tissue available from one of the patients showed somatic loss of the MBD4 wildtype allele and a high tumor mutation burden.
In an individual (UM293) with uveal melanoma-1 (UVM1; 606660), Derrien et al. (2021) identified a germline heterozygous c.1402C-T transition in the MBD4 gene, resulting in an arg468-to-trp (R468W) substitution. The variant was found in 1 of 251,308 alleles (3.98 x 10(-6)) in the gnomAD database (v.2.1.1). In vitro functional expression studies showed that the mutant protein lacked glycosylase activity, consistent with a loss of function. Tumor tissue available from the patients showed somatic loss of the MBD4 wildtype allele and a high tumor mutation burden.
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