HGNC Approved Gene Symbol: BAP1
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38): 3:52,401,008-52,410,008 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.1 | {Uveal melanoma, susceptibility to, 2} | 606661 | Autosomal dominant | 3 |
| Kury-Isidor syndrome | 619762 | Autosomal dominant | 3 | |
| Tumor predisposition syndrome 1 | 614327 | Autosomal dominant | 3 |
BAP1 encodes a nuclear ubiquitin carboxy-terminal hydrolase (UCH), one of several classes of deubiquitinating enzymes. BAP1 contains binding domains for BRCA1 (113705) and BARD1 (601593), which form a tumor suppressor heterodimeric complex, and HCFC1 (300019), which interacts with histone-modifying complexes during cell division. BAP1 also interacts with ASXL1 (612990) to form the Polycomb group repressive deubiquitinase complex (PR-DUB), which is involved in stem cell pluripotency and other developmental processes (summary by Harbour et al., 2010).
Nagase et al. (1996) isolated a BAP1 cDNA, designated KIAA0272.
Jensen et al. (1998) carried out a yeast 2-hybrid screen to identify proteins that interact with the RING finger domain of BRCA1 (113705). They recovered mouse embryo and human adult B-cell cDNAs encoding a protein that they designated 'BRCA1-associated protein-1,' or BAP1. The N-terminal 240 amino acids of the predicted 729-amino acid human protein show homology to ubiquitin C-terminal hydrolases (UCHs; see UCHL3, 603090), thiol proteases that catalyze proteolytic processing of ubiquitin. In addition, BAP1 contains an acidic region, a highly charged C-terminal region, and 2 putative nuclear localization signals. Recombinant BAP1 had UCH activity in vitro. By coimmunoprecipitation and immunofluorescence studies, Jensen et al. (1998) demonstrated that BAP1 and BRCA1 associate in vivo and have overlapping subnuclear localization patterns. However, BAP1 failed to bind to BRCA1 proteins with germline mutations of the RING finger domain found in breast cancer kindreds. BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth. Northern blot analysis indicated that BAP1 is expressed as a 4-kb mRNA in all human tissues. An additional 4.8-kb transcript is present in testis. Northern blot analysis and in situ hybridization revealed that BAP1 and BRCA1 are temporally and spatially coexpressed during murine breast development and remodeling.
Nagase et al. (1996) mapped the BAP1 gene to chromosome 3 by analysis of radiation hybrids.
By fluorescence in situ hybridization, Jensen et al. (1998) mapped the BAP1 gene to 3p21.3, a region of loss of heterozygosity for breast cancer as well as a region frequently deleted in lung carcinomas.
Jensen et al. (1998) found intragenic homozygous rearrangements and deletions of BAP1 in lung carcinoma cell lines. They proposed that BAP1 is a tumor suppressor gene that functions in the BRCA1 growth control pathway.
Dey et al. (2012) showed that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (614286). Analysis of knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor-1 (HCF1; 300019), O-linked N-acetylglucosamine transferase (OGT; 300255), and the polycomb group proteins ASXL1 and ASXL2 (612991) in vivo. OGT and HCF1 levels were decreased by BAP1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML; 607785), so an ASXL/BAP1 complex may suppress CMML.
Bononi et al. (2017) discovered that BAP1 localizes at the endoplasmic reticulum. There, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3; 147267), modulating calcium release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 +/- carriers cause reduction both of IP3R3 levels and of Ca(2+) flux, preventing BAP1 +/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. Bononi et al. (2017) proposed that the high incidence of cancers in BAP1 +/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Bononi et al. (2017) concluded that their data provided a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.
He et al. (2019) showed that Bap1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase Rnf2 (608985), which silences genes by monoubiquitinating histone H2a (see 613499), promoted apoptosis in Bap1-deficient cells by suppressing expression of the prosurvival genes Bcl2 (151430) and Mcl1 (159552). In contrast, Bap1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf (156845). Thus, He et al. (2019) concluded that BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss promotes tumorigenesis only in cells that do not engage an RNF2-dependent apoptotic program.
Xiong et al. (2020) found that Bap1 facilitated expression of Hoxa1 (142955), which was required for self-renewal of mouse hematopoietic stem cells (HSCs). Ttll5 (612268) and Ttll7 (618813) glutamylated Bap1 at glu651 in HSCs, whereas Ccp3 (617346) removed Bap1 glutamylation. Bap1 glutamylation promoted its interaction with Ube2o (617649) and accelerated lys48-linked ubiquitination of Bap1 for its degradation. Degradation of Bap1 suppressed Hoxa1 expression, thereby enhancing HSC self-renewal and hematopoiesis.
Somatic BAP1 Mutations
BAP1 exhibits tumor suppressor activity in cancer cells, and BAP1 mutations have been reported in a small number of breast and lung cancer samples. Harbour et al. (2010) used exome capture coupled with massively parallel sequencing to search for metastasis-related mutations in highly metastatic uveal melanomas (see UVM2, 606661). Inactivating somatic mutations were identified in the BAP1 gene on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin C-terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele. Harbour et al. (2010) concluded that their findings implicated loss of BAP1 in uveal melanoma metastasis.
By studying copy number alterations followed by candidate gene sequencing of 53 primary malignant pleural mesothelioma (156240) samples, Bott et al. (2011) identified the BAP1 gene on chromosome 3p21.1 as a commonly somatically inactivated gene. Twelve (23%) of 53 tumors had nonsynonymous mutations, and 16 (30%) had at least single copy genomic loss of the BAP1 locus. Tumors with mutations showed loss of nuclear staining for BAP1. BAP1 losses were confirmed in an independent collection of MPM tumors. The somatic nature of the mutations was confirmed in all tumors that had matched normal tissue available. Knockdown of BAP1 in mesothelioma cell lines expressing wildtype BAP1 resulted in proliferation defects with an accumulation of cells in S phase and also downregulated E2F (see, e.g., 189971)-responsive genes. Given the known role of BAP1 in regulatory ubiquitination of histones, the findings suggested transcriptional deregulation as a pathogenic mechanism.
By sequencing of the BAP1 gene in 156 tumors from patients with sporadic melanocytic neoplasms, Wiesner et al. (2011) found somatic mutations in 13 (40%) uveal melanomas, 2 (11%) atypical Spitz tumors, and 3 (5%) cutaneous melanomas (155600). Two of 5 sporadic cutaneous melanomas that arose in nevi harbored BAP1 mutations, and in both cases, the BAP1 mutations were absent in the nevus portion, suggesting that loss of function of BAP1 may have a role in progression from nevus to melanoma in some cases. The 2 atypical Spitz tumors lacked BAP1 expression and harbored a BRAF mutation (V600E; 164757.0001), suggesting that biallelic inactivation of BAP1 is associated with a distinct type of melanocytic neoplasm. Finally, all the uveal melanomas with BAP1 mutations also carried mutations at codon 209 in either GNAQ (600998) or GNA11 (139313).
Pena-Llopis et al. (2012) provided evidence that BAP1 can act as a tumor suppressor gene in clear cell renal cell carcinoma (ccRCC; see 144700). The authors used whole-genome and exome sequencing of ccRCC as well as analyses of mutant allele ratios of a murine tumorgraft to identify putative 2-hit tumor suppressor genes. BAP1 was found to be somatically mutated in 24 (14%) of 176 tumors, and most mutations were predicted to truncate the protein. In a cell line with a missense BAP1 mutation, expression of wildtype BAP1 repressed cell proliferation without causing apoptosis. In this cell line, the majority of BAP1 cofractionated with and bound to HCFC1. Mutations disrupting the HCFC1 binding motif impaired BAP1-mediated suppression of cell proliferation, but not its deubiquitination of monoubiquitinated histone 2A. BAP1 loss sensitized RCC cells in vitro to genotoxic stress. Although mutations in BAP1 and PBRM1 (606083) anticorrelated in renal cell tumors, the few tumors that had combined loss of BAP1 and PBRM1 were associated with rhabdoid features. Moreover, BAP1 loss was associated with high tumor grade.
Dey et al. (2012) identified a patient with a somatic frameshift mutation that causes premature termination within the UCH catalytic domain of BAP1. The patient with the somatic BAP1 mutation presented with refractory cytopenias and multilineage dysplasia, similar to the multilineage dysplasia and cytopenias seen in their murine model. No other mutations in known MDS genes were identified.
Jiao et al. (2013) detected somatic BAP1 mutations in 8 of 32 (25%) intrahepatic cholangiocarcinomas (615619) in a discovery screen and in 5 of 32 (16%) independent intrahepatic cholangiocarcinomas in the prevalence screen. Chan-on et al. (2013) identified somatic BAP1 mutations in 9 of 86 (10.5%) non-O.viverrini cholangiocarcinomas and in 3 of 108 (2.8%) O. viverrini-related cholangiocarcinomas.
Tumor Predisposition Syndrome 1
Using array-based comparative genomic hybridization, Wiesner et al. (2011) found loss of chromosome 3p in 50% of skin tumors from 3 affected individuals in a family with tumor predisposition syndrome-1 (TPDS1; 614327), suggesting that this was a second hit resulting in the elimination of the remaining wildtype allele of a mutated tumor suppressor gene in this chromosomal region. Haplotype analysis showed segregation of the maternal allele in affected family members of 2 generations, and sequence analysis of this region identified a heterozygous germline mutation in the BAP1 gene (603089.0001) that segregated with the phenotype. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and in a uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. Immunohistochemical studies showed loss of BAP1 nuclear expression in the melanocytic neoplasms. Molecular analysis of a second family with a similar phenotype identified a different heterozygous germline mutation in the BAP1 gene (603089.0002). Somatic inactivation of the remaining allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in a uveal melanoma, and in a cutaneous melanoma from 1 patient. In addition, 37 (88%) of 42 tumors in both families showed a somatic V600E mutation in the BRAF gene (164757.0001). Notably, the families had a low number of melanomas compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low.
In 2 unrelated families with a tumor predisposition syndrome characterized mainly by the development of asbestos-related malignant mesothelioma, Testa et al. (2011) identified 2 different heterozygous mutations in the BAP1 gene (603089.0003 and 603089.0004, respectively) that segregated with the phenotype. Array-comparative genomic hybridization had found loss of BAP1 at 3p21 in 2 malignant mesothelioma tumors from these families, and subsequent linkage analysis identified an inherited susceptibility locus on chromosome 3p21. Tumor tissue showed loss of BAP1 nuclear expression by immunohistochemistry. The findings were consistent with somatic loss of the second BAP1 allele in tumor tissue. Further analysis of 26 germline DNA samples from patients with sporadic mesothelioma found that 2 carried heterozygous BAP1 deletions (603089.0005 and 603089.0006, respectively). Each of these patients also had a history of uveal melanoma.
Abdel-Rahman et al. (2011) identified a heterozygous germline mutation in the BAP1 gene (603089.0007) in 1 of 53 probands with uveal melanoma and evidence of a familial cancer syndrome who were screened specifically for BAP1 mutations. In this family, the mutation segregated with various types of cancer, including lung adenocarcinoma, cutaneous melanoma, and meningioma. Tumor tissue showed LOH for the BAP1 gene.
In affected members of a large family with a tumor predisposition syndrome characterized mainly by renal cell carcinoma (RCC), Popova et al. (2013) identified a heterozygous germline mutation in the BAP1 gene (603089.0008). The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. Subsequently, sequence analysis identified heterozygous truncating mutations in the BAP1 gene (see, e.g., 603089.0009 and 603089.0010) in 11 (18%) of 60 unrelated families with either uveal melanoma, cutaneous melanoma, or mesothelioma. A total of 33 individuals were diagnosed with these 3 cancers in diverse associations; 14 individuals had other cancers, including renal, lung, breast, prostatic, thyroid, and bladder carcinomas. Nine RCCs were reported in 6 of the 11 families with BAP1 mutations, indicating that RCC should be added to the tumor spectrum of this syndrome. However, no BAP1 mutations were detected in a separate series of 32 French families with renal cell carcinoma, suggesting that germline BAP1 mutations rarely explain families affected only with RCC.
In 6 affected members of a large multigenerational kindred (K4) of European origin with TPDS1, Carbone et al. (2015) identified a heterozygous germline frameshift mutation in the BAP1 gene (c.1717delC; 603089.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. Carbone et al. (2015) emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers because early detection and diagnosis can lead to effective treatment.
Melanoma, Uveal, Susceptibility to, 2
In 2 unrelated Caucasian men with bilateral uveal melanoma-2 (UVM2; 606661), Yu et al. (2020) identified germline heterozygous frameshift mutations in the BAP1 gene (603089.0015 and 603089.0016). Functional studies of the variants were not performed. Cytogenetic profile of tumor tissue showed somatic changes affecting chromosomes 3, 6, and 8. Family history in patient 1 was significant for cancer, although familial genetic segregation studies were not conducted in either proband. The patients did not have other tumors or systemic metastasis.
Kury-Isidor Syndrome
In 8 unrelated patients (patients 1-4 and 7-10) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified de novo heterozygous missense mutations in the BAP1 gene (see, e.g., 602089.0011-601089.0014). The patients were ascertained through collaborative efforts such as the GeneMatcher Program, and the phenotype was compiled after the variants were identified by exome sequencing. All the mutations occurred at conserved residues in the catalytic ubiquitin C-terminal hydrolase domain; none were present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that some of the variants tested (P12T, 603089.0011; C91R, 603089.0013; and H169R, 603089.0014) were unable to rescue BAP1 activity, as measured by increased BAP1 H2AK119ub substrate levels. Rescue with another variant (P12A; 603089.0012) was similar to controls for that particular substrate. All variants, including P12A, were unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data suggested that the BAP1 mutations were unable to compensate H2A deubiquitination of substrates in BAP1-null cells, consistent with a loss-of-function effect. Of note, all the BAP1 variants localized properly to the nucleus in transfected cells. T cells derived from 2 patients carrying the P12T and C91S mutations showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect for BAP1. CHIP-seq analysis indicated that the variants induced genomewide chromatin state alterations in the 2 patient cell lines; there was also some evidence of proteosome perturbation. Kury et al. (2022) concluded that BAP1 missense variants alter chromatin remodeling through abnormal histone ubiquitination, leading to transcriptional dysregulation of developmental genes. None of the patients developed tumors. The authors noted that BAP1 mutations that predispose to tumor syndrome are truncating or splice-site mutations; the missense mutations identified in patients with KURIS are loss-of-function and may disrupt the deubiquitinase activity without altering other protein-protein interactions. Some of the patients, including 3 additional patients (patients 5, 6, and 11) with variable developmental abnormalities associated with de novo missense BAP1 variants identified in the study, had additional genetic variants of uncertain significance that may have contributed to the phenotype.
In 4 affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of melanocytic skin tumors, Wiesner et al. (2011) identified a germline heterozygous 1-bp deletion (1305delG) in exon 13 of the BAP1 gene, resulting in a frameshift. The mutation was found after tumor analysis showed loss of chromosome 3p in 50% of tumors and haplotype analysis showed segregation of a maternal allele in the 3p21 region in affected family members of 2 generations. All 4 had multiple melanocytic tumors, and 1 had a uveal melanoma. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and the uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. The findings were consistent with germline predisposition to development of the disorder with a second somatic hit in a tumor suppressor gene resulting in tumor development. Immunohistochemical studies showed loss of BAP1 nuclear expression in all the melanocytic neoplasms. Most of the tumors also carried a somatic V600E mutation in the BRAF gene (164757.0001). Notably, none of the patients in this family developed cutaneous melanoma despite the large number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low.
In affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of melanocytic skin tumors, Wiesner et al. (2011) identified a heterozygous A-to-G transition removing the acceptor splice site of the last exon (2057-2A-G). Analysis of cDNA showed that the last intron was not removed by splicing. One mutation carrier developed a uveal melanoma, and 3 developed cutaneous melanoma. Somatic inactivation of the remaining BAP1 allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in the 1 uveal melanoma, and in a cutaneous melanoma from 1 patient. A metastatic melanoma from another family member did not show LOH for BAP1, but no additional tissue was available to investigate alternative mechanisms of BAP1 inactivation. In contrast, microscopic examination of common acquired flat nevi showed small uniform melanocytes and strong nuclear expression of BAP1. Most of the tumors also carried a somatic V600E mutation in the BRAF gene (164757.0001). Notably, only 3 patients in this family developed cutaneous melanoma, compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low.
In affected members of a 3-generation Wisconsin family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of malignant mesothelioma, Testa et al. (2011) identified a heterozygous germline A-to-G transition in the splice acceptor site of intron 6 of the BAP1 gene. Transfection of mammalian cells with this mutation resulted in an aberrant splice product lacking exon 8 and a frameshift predicted to result in a premature stop codon and nonsense-mediated decay. Tumor tissue from 3 patients showed complete loss of BAP1, consistent with somatic loss of the wildtype allele, and immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Five mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 1 each had breast, ovarian, and renal cancer. The mutation was identified after tumor tissue showed loss of BAP1 at 3p21 with subsequent performance of linkage analysis in this family.
In affected members of a 2-generation family from Louisiana with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of malignant mesothelioma, Testa et al. (2011) identified a heterozygous germline C-to-T transition in exon 16 of the BAP1 gene, resulting in a gln684-to-ter (Q684X) substitution. Immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Six mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 2 developed skin cancer (squamous cell and basal cell, respectively), and 1 developed pancreatic cancer. Two family members with prostate cancer did not carry the mutation.
In a patient with tumor predisposition syndrome-1 (TPDS1; 614327) who developed malignant mesothelioma and a uveal melanoma, Testa et al. (2011) identified a heterozygous germline 1-bp deletion (1832delC) in exon 13 of the BAP1 gene, resulting in a frameshift and truncation upstream of the BAP1 nuclear localization signal.
In a patient with tumor predisposition syndrome-1 (TPDS1; 614327) who developed malignant mesothelioma and uveal melanoma, Testa et al. (2011) identified a heterozygous germline 4-bp deletion (2008delTCAC) in exon 14 of the BAP1 gene, resulting in a frameshift and truncation upstream of the BAP1 nuclear localization signal.
In affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327), Abdel-Rahman et al. (2011) identified a heterozygous 799C-T transition in the BAP1 gene, resulting in a gln267-to-ter (Q267X) substitution proximal to the nuclear localization region. The mutation was not found in 1,000 genomes. The proband was ascertained due to the onset of uveal melanoma at age 52 years, and she also had lung adenocarcinoma. Three additional living family members with cancer also carried the mutation: 1 had cutaneous melanoma, 1 had meningioma, and 1 had uveal melanoma and neuroendocrine carcinoma. There were 2 deceased obligate carriers, who had a history of abdominal adenocarcinoma, likely ovarian, and mesothelioma, respectively. One additional mutation carrier was cancer-free at age 55 years. Tumor tissue from lung adenocarcinoma, meningioma, and uveal melanoma of 3 patients all showed somatic loss of heterozygosity for the BAP1 gene, and all had decreased BAP1 nuclear expression using immunohistochemical studies. The findings were consistent with biallelic inactivation of the BAP1 gene. Abdel-Rahman et al. (2011) concluded that this family had a hereditary cancer predisposition syndrome that increases the risk of several different types of tumors. The proband in this family was the only 1 of 53 unrelated patients with uveal melanoma and evidence of a familial cancer syndrome screened for BAP1 mutations who was found to carry a mutation, suggesting that is it a rare cause of hereditary uveal melanoma.
In affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of renal cell carcinoma, Popova et al. (2013) identified a heterozygous c.277A-G transition in the BAP1 gene, predicted to result in a thr93-to-ala (T93A) substitution at a conserved residue close to the active site of the ubiquitin domain. The mutation also created a new splice acceptor site within exon 5, and patient cells showed 2 transcripts: c.256_277del, resulting in premature termination (Ile87MetfsTer4) (80% of transcripts) and the missense mutation T93A (20% of transcripts). Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing.
In 2 affected members of a family with tumor predisposition syndrome-1 (TPDS; 614327) characterized mainly by uveal melanoma and mesothelioma, Popova et al. (2013) identified a heterozygous 1-bp deletion (c.1654delG) in the BAP1 gene, resulting in a frameshift and premature termination (Asp552IlefsTer19). One obligate mutation carrier had a renal cell carcinoma.
In 2 sibs with tumor predisposition syndrome-1 (TPDS1; 614327) characterized by renal cell carcinoma, mesothelioma, lung cancer, and cutaneous melanoma, Popova et al. (2013) identified a heterozygous 2-bp deletion (c.78_79delGG) in the BAP1 gene, resulting in a frameshift and premature termination (Val27AlafsTer41).
In a 10-year-old girl (patient 1) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.34C-A transversion (c.34C-A, NM_004656.3) in the BAP1 gene, resulting in a pro12-to-thr (P12T) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the P12T variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect. T cells derived from the patient carrying the P12T mutation showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect on BAP1 deubiquitination activity. The patient walked at 18 months of age and had early speech delay, but later had good conversation. She had 3 febrile seizures as an infant; brain imaging was normal. She also had behavioral abnormalities and was noted to be emotional, sensitive, and have poor attention.
In a 3-year-old boy (patient 2) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.34C-G transversion (c.34C-G, NM_004656.3) in the BAP1 gene, resulting in a pro12-to-ala (P12A) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the P12A variant was able to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. However, the mutation was unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. The patient had delayed walking at age 19 months, speech delay, and autistic features. Other features included frontal bossing, finger syndactyly, astigmatism, bicuspid aortic valve, and recurrent ear infections.
In 2 unrelated children (patients 7 and 8) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.271T-C transition (c.271T-C, NM_004656.3) in the BAP1 gene, resulting in a cys91-to-arg (C91R) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. Patient 7 was a 2-year-old boy with walking at age 17 months and mild speech delay. The pregnancy was complicated by polyhydramnios and cystic hygroma. He had coarse facial features with mild dysmorphism. Patient 8 was a 4-year-old girl with delayed walking, poor speech, hypotonia, behavioral problems, and dysmorphic facies. She also had ocular abnormalities, including exudative vitreoretinopathy and high myopia. In addition to the BAP1 variant, patient 8 carried a truncating R731X variant in the CTNNA1 gene (116805) that was maternally inherited.
In 2 unrelated patients (patients 9 and 10) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.506A-G transition (c.506A-G, NM_004656.3) in the BAP1 gene, resulting in a his169-to-arg (H169R) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. Patient 9 was a 16-year-old boy with mild developmental delay, behavioral problems noted as sensitivity, seizures, distal skeletal anomalies, and patchy alopecia. He also carried biallelic variants in the NCSTN gene (605254). Patient 10 was an 8-year-old girl with mild global developmental delay, poor speech, a history of seizures, behavioral abnormalities, and mild dysmorphic features. She carried a mitochondrial variant of uncertain significance that showed low (2%) heteroplasmy.
Tumor Predisposition Syndrome 1
In 6 affected members of a large kindred (K4) of European origin with tumor predisposition syndrome-1 (TPDS1; 614327), Carbone et al. (2015) identified a heterozygous germline 1-bp deletion (c.1717delC) in exon 13 of the BAP1 gene, resulting in a frameshift and premature termination (Leu573fsTer3). The mutation, which was found by exome sequencing and confirmed, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. Multiple family members spanning at least 6 generations showed various types of cancer, including malignant mesothelioma, uveal melanoma, basal cell carcinoma, leiomyosarcoma, renal cell carcinoma, and cutaneous melanoma. One mutation carrier had breast cancer. There was high penetrance of cancer manifestation by age 55 years. Carbone et al. (2015) emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers, because early detection and diagnosis can lead to effective treatment.
Melanoma, Uveal, Susceptibility to, 2
In a 48-year-old Caucasian man (patient 1) with bilateral uveal melanoma-2 (UVM2; 606661), Yu et al. (2020) identified a germline heterozygous c.1717delC mutation in the BAP1 gene. Functional studies of the variant were not performed. Cytogenetic profile of tumor tissue showed somatic disomy of chromosomes 3, 6, and 8. Family history was significant for ovarian and bladder cancer in his mother and pancreatic cancer in his maternal great-grandfather, although familial genetic segregation studies were not conducted. The patient did not have other tumors or systemic metastasis.
In a 54-year-old Caucasian man (patient 2) with uveal melanoma-2 (UVM2; 606661), Yu et al. (2020) identified a germline heterozygous 1-bp deletion (c.79delG) in exon 3 of the BAP1 gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and familial segregation studies were not performed. The patient had enucleation of 1 eye due to uveal melanoma and later was found to have a melanoma in the ciliary body of the other eye. There was no evidence of systemic metastasis. Cytogenetic profile of the tumor tissue showed somatic chromosome 3 monosomy, chromosome 6 disomy, and chromosome 8q amplification.
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