Alternative titles; symbols
HGNC Approved Gene Symbol: ATP2B2
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:10,324,023-10,708,007 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | {Deafness, autosomal recessive 12, modifier of} | 601386 | Autosomal recessive | 3 |
| Deafness, autosomal dominant 82 | 619804 | Autosomal dominant | 3 |
The Ca(2+)-ATPases are a family of plasma membrane pumps encoded by at least 4 genes: ATP2B1 (108731) on chromosome 12q21; ATP2B2; ATP2B3 (300014) on Xq28; and ATP2B4 (108732) on 1q25.
Brandt et al. (1992) isolated and characterized a cDNA for the human PMCA2 gene from a human fetal brain cDNA library. The 1,190-amino acid protein showed greater than 98% sequence identity to the rat protein.
By PCR, Brandt et al. (1992) detected PMCA2 expression in brain, liver, spinal cord, and adrenal gland. There were 2 PCR products in spinal cord, suggesting the presence of PMCA2 splice variants.
By RT-PCR, Santiago-Garcia et al. (1996) found variable expression of the PMCA and SERCA (see 108730) genes during development of human fetal heart. PMCA2 was not detected in placenta or in fetal heart at the 3 stages tested, but 3 splice variants of PMCA2 were detected in adult atrium.
Street et al. (1998) noted that the ATP2B2 gene undergoes alternative splicing. All 4 ATP2B proteins are predicted to have 10 transmembrane-spanning domains with approximately 80% of the protein mass located in the cytoplasm. The intracellular loop between T2 and T3 encodes the transducing domain that couples ATP hydrolysis with calcium translocation. The largest intracellular loop, between T4 and T5, includes the phosphoenzyme-forming residue and the nucleotide-binding domain. The intracellular C terminus contains the calmodulin-binding, protein kinase C, cAMP-dependent kinase and acidic phospholipid regulatory domains.
Elwess et al. (1997) found that the alternative splice variants PMCA2a and PMCA2b had much higher affinity for calmodulin than the corresponding forms of PMCA4. At a high calmodulin concentration, PMCA2b showed higher calcium affinity. The calcium affinity was localized to the C terminus. Elwess et al. (1997) concluded that the PMCA2 variants maintain a low free cytosolic calcium concentration.
Street et al. (1998) found Atp2b2 expression in mouse auditory and vestibular hair cells, suggesting that the channel provides the means to remove calcium from stereocilia.
By yeast 2-hybrid analysis of a human brain cDNA expression library, DeMarco et al. (2002) found that PCMA2b interacted with NHERF2 (SLC9A3R2; 606553). Coimmunoprecipitation analysis indicated that the interaction was specific and selective, in that PCMA4b did not interact with either NHERF2 or NHERF1 (SLC9A3R1; 604990), and PCMA2b preferred NHERF2 over NHERF1. Fluorescence-tagged PCMA2b was expressed at the apical membrane of canine kidney epithelial cells, where it colocalized with apically targeted NHERF2. DeMarco et al. (2002) hypothesized that the PCMA2b-NHERF2 interaction may allow the assembly of PMCA2b in a multiprotein Ca(2+) signaling complex.
Chicka and Strehler (2003) found that PMCA2b localized to both the apical and basolateral membranes of polarized epithelial cells. Different splice variants of the protein showed differential membrane targeting.
Using the PMCA2 cDNA to probe Southern blots of human-rodent somatic cell hybrid DNAs, Brandt et al. (1992) mapped the PMCA2 gene to human chromosome 3. By a combination of fluorescence in situ hybridization, analysis of somatic cell hybrids, and genetic linkage analysis in CEPH families, Wang et al. (1994) confirmed assignment of the ATP2B2 gene to 3p26-p25.
Richards et al. (1993) reported that the PMCA2 gene, which is located on 3p, is situated centromeric to the gene (VHL; 608537) for von Hippel-Lindau disease (193300). They reported other results that excluded PMCA2 as the site of the mutation in VHL.
In 11 patients from 5 unrelated families with autosomal dominant deafness-82 (DFNA82; 619804), Smits et al. (2019) identified heterozygous nonsense, splice site, or frameshift mutations in the ATP2B2 gene (see, e.g., 108733.0002-108733.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, occurred de novo in 2 unrelated patients and segregated with an autosomal dominant pattern of inheritance in the 3 remaining families. Functional studies of the variants and studies of patient cells were not performed, but all were predicted to result in a loss of ATP2B2 function and haploinsufficiency. Genetic analysis showed that most of the patients also carried heterozygous variants of uncertain significance in the CDH23 gene (605516) or in other genes that may have modified the phenotype, although the authors excluded a major effect of these variants and concluded that the ATP2B2 mutations are the underlying cause of monogenic deafness in these families. The ATP2B2 mutations affected the ortholog of the rat Atp2b2 w/a isoform, which is expressed in inner and outer hair cells; mice with mutations in the Atp2b2 gene have progressive deafness (see ANIMAL MODEL). Smits et al. (2019) concluded that loss of ATP2B2 function in the ear may result in calcium cytotoxicity leading to degeneration of inner and outer hair cells and progressive hearing loss.
Street et al. (1998) demonstrated that the deafwaddler (dfw) mouse mutant, which is deaf and displays vestibular/motor imbalance, has a mutation in the Atp2b2 gene. An A-to-G nucleotide transition in dfw DNA caused a glycine-to-serine substitution at a highly conserved amino acid position, whereas a second mutant allele carried a 2-bp deletion that caused a frameshift predicted to result in a truncated protein. In the cochlea, the Atp2b2 protein was localized to stereocilia and the basolateral wall of hair cells in wildtype mice, but was not detected in deafwaddler mice. The findings indicated that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia as well as neurotransmitter release from the basolateral membrane. These mutations affecting Atp2b2 were the first to be found in a mammalian plasma membrane calcium pump and defined a new class of deafness genes that directly affect hair-cell physiology.
PMCA2 exhibits a highly restricted tissue distribution, suggesting that it serves more specialized physiologic functions than some of the other PMCA isoforms. A unique role in hearing is suggested by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells. To analyze the physiologic role of PMCA2, Kozel et al. (1998) produced PMCA2-deficient mice by gene targeting. Homozygous PMCA2-null mice grew more slowly than heterozygous and wildtype mice and exhibited an unsteady gait and difficulties in maintaining balance. Histologic analysis of the cerebellum and inner ear of mutant and wildtype mice showed that null mutants have slightly increased numbers of Purkinje neurons (in which PMCA2 is highly expressed), a decreased thickness of the molecular layer, an absence of otoconia in the vestibular system, and a range of abnormalities of the organ of Corti. Analysis of auditory-evoked brainstem responses showed that homozygous mutants were deaf and that heterozygous mice had a significant hearing loss. These data demonstrated that PMCA2 is required for both balance and hearing and suggested that it may be a major source of the calcium used in the formation and maintenance of otoconia.
Reinhardt et al. (2004) noted that the PMCA2bw isoform is expressed approximately 100-fold during lactation, and that expression levels correlate with milk production and calcium secretion. They found that mice homozygous for the loss of Pmca2 produced milk with 60% less calcium than that of heterozygous or wildtype mice. There was no alteration in whole-body calcium metabolism in the null mice. The findings indicated that the Pmca2bw isoform, which allows the enzyme to function as a high affinity calcium extrusion system on the apical membrane, is necessary to produce the high levels of calcium in milk, and that it occurs by direct secretion by the calcium pump.
Bortolozzi et al. (2010) characterized Tommy (tmy) mutant mice, which were generated in an N-ethyl-N-nitrosourea mutagenesis screen. Tmy/tmy mice were profoundly deaf at birth and were smaller than their littermates. They developed severe ataxia, with hesitant wobbly gait and frequent hyperextension of the rear limbs. Tmy heterozygous mice developed deafness by 12 weeks of age, with full penetrance by 30 weeks. Bortolozzi et al. (2010) identified the tmy mutation as a nonconservative G-to-A transition in exon 7 of the Atp2b2 gene, resulting in a gln629-to-lys (E629K) substitution in Atp2b2 w/a, the Atp2b2 isoform expressed in hair cells (the substitution corresponds to E584K in the Atp2b2 z/b isoform, which lacks the 45-amino acid insertion in Atp2b2 w/a). Expression of mutant Atp2b2 in Chinese hamster ovary cells caused impaired calcium extrusion, with inhibition of long-term, nonstimulated calcium export. Recordings of neonate organotypic cultures of utricle sensory epithelium confirmed impaired calcium export in both tmy/tmy and tmy/+ mice following rapid calcium release. Immunofluorescence analysis of the organ of Corti in tmy/tmy mice showed a progressive base to apex degeneration of hair cells after postnatal day 40.
In 3 of 5 sibs, born of consanguineous parents, with autosomal recessive deafness (DFNB12; 601386) caused by a homozygous phe1888-to-ser substitution in the CDH23 gene (F1888S; 605516.0010), Schultz et al. (2005) identified a heterozygous 2075G-A transition in exon 12 of the ATP2B2 gene, resulting in a val586-to-met (V586M) substitution. The 3 sibs heterozygous for V586M had severe to profound hearing loss affecting all frequencies, whereas the other 2 sibs had high-frequency hearing loss. Schultz et al. (2005) suggested that V586M modifies the severity of sensorineural hearing loss.
Lek et al. (2016) questioned the validity of this variant as a modifier of the severity of deafness because it has a high allele frequency (0.0467) in the Latino population in the ExAC database.
In a 24-year-old Dutch woman (family W18-0138) with onset of autosomal dominant deafness-82 (DFNA82; 619804) at age 3 years, Smits et al. (2019) identified a de novo heterozygous 1-bp deletion (c.955delG, NM_001001331.2) in the ATP2B2 gene, resulting in a frameshift and premature termination (Ala319fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database (version r2.02) or among 20,000 in-house control exomes. Genetic analysis also identified a heterozygous missense variant (N1282S) of uncertain significance in the CDH23 gene (605516) that may have had a modifying effect on the phenotype. Functional studies of the variant and studies of patient cells were not performed, but the ATP2B2 variant was predicted to result in a loss of function and haploinsufficiency.
In 3 affected members spanning 3 generations of a large family (W18-0139) with autosomal dominant deafness-82 (DFNA82; 619804), Smits et al. (2019) identified a heterozygous c.2329C-T transition (c.2329C-T, NM_00100133.1.2) in the ATP2B2 gene, resulting in an arg777-to-ter (R777X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two family members had early-onset deafness, whereas 1 affected family member had onset of hearing loss at age 55 years. Genetic analysis also identified heterozygous variants of uncertain significance in the CDH23 gene (605516) that may have had a modifying effect on the phenotype: the 2 family members with early-onset hearing loss carried a synonymous CDH23 variant (c.8022G-A), whereas the family member with later onset carried a heterozygous missense CDH23 variant (N1282S). Functional studies of the variant and studies of patient cells were not performed, but the ATP2B2 variant was predicted to result in a loss of function and haploinsufficiency.
In a 6-year-old girl (family W17-4352) with onset of autosomal dominant deafness-82 (DFNA82; 619804) at age 2 years, Smits et al. (2019) identified a de novo heterozygous c.1963G-T transversion (c.1963G-T, NM_001001331.2) in the ATP2B2 gene, resulting in a glu655-to-ter (E655X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient also carried 2 variants in the DNM1 gene (602377) that were not thought to be pathogenic, as well as a heterozygous missense variant (R2304Q) in the CDH23 gene (605516) that may have had a modifying effect on the phenotype. Functional studies of the variant and studies of patient cells were not performed, but the ATP2B2 variant was predicted to result in a loss of function and haploinsufficiency.
In 4 affected members of a 3-generation family (family W17-0883) with autosomal dominant deafness-82 (DFNA82; 619804), Smits et al. (2019) identified a heterozygous c.1998C-A transversion (c.1998C-A, NM_001001331.2) in the ATP2B2 gene, resulting in a cys666-to-ter (C666X) substitution. Onset of hearing loss occurred between ages 2 and 6 years. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Genetic analysis indicated that 2 affected family members also carried a heterozygous predicted splice site variant in the CDH23 gene (605516) that may have had a modifying effect on the phenotype; however, this CDH23 variant was inherited from an unaffected mother. Functional studies of the variant and studies of patient cells were not performed, but the ATP2B2 variant was predicted to result in a loss of function and haploinsufficiency.
Bortolozzi, M., Brini, M., Parkinson, N., Crispino, G., Scimemi, P., De Siati, R. D., Di Leva, F., Parker, A., Ortolano, S., Arslan, E., Brown, S. D., Carafoli, E., Mammano, F. The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice. J. Biol. Chem. 285: 37693-37703, 2010. [PubMed: 20826782] [Full Text: https://doi.org/10.1074/jbc.M110.170092]
Brandt, P., Ibrahim, E., Bruns, G. A. P., Neve, R. L. Determination of the nucleotide sequence and chromosomal localization of the ATP2B2 gene encoding human Ca(2+)-pumping ATPase isoform PMCA2. Genomics 14: 484-487, 1992. [PubMed: 1427863] [Full Text: https://doi.org/10.1016/s0888-7543(05)80246-0]
Brandt, P., Neve, R. L., Kammesheidt, A., Rhoads, R. E., Vanaman, T. C. Analysis of the tissue-specific distribution of mRNAs encoding the plasma membrane calcium-pumping ATPases and characterization of an alternately spliced form of PMCA4 at the cDNA and genomic levels. J. Biol. Chem. 267: 4376-4385, 1992. [PubMed: 1531651]
Chicka, M. C., Strehler, E. E. Alternative splicing of the first intracellular loop of plasma membrane Ca2+-ATPase isoform 2 alters its membrane targeting. J. Biol. Chem. 278: 18464-18470, 2003. [PubMed: 12624087] [Full Text: https://doi.org/10.1074/jbc.M301482200]
DeMarco, S. J., Chicka, M. C., Strehler, E. E. Plasma membrane Ca(2+) ATPase isoform 2b interacts preferentially with Na+/H+ exchanger regulatory factor 2 in apical plasma membranes. J. Biol. Chem. 277: 10506-10511, 2002. [PubMed: 11786550] [Full Text: https://doi.org/10.1074/jbc.M111616200]
Elwess, N. L., Filoteo, A. G., Enyedi, A., Penniston, J. T. Plasma membrane Ca2+ pump isoforms 2a and 2b are unusually responsive to calmodulin and Ca2+. J. Biol. Chem. 272: 17981-17986, 1997. [PubMed: 9218424] [Full Text: https://doi.org/10.1074/jbc.272.29.17981]
Kozel, P. J., Friedman, R. A., Erway, L. C., Yamoah, E. N., Liu, L. H., Riddle, T., Duffy, J. J., Doetschman, T., Miller, M. L., Cardell, E. L., Shull, G. E. Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca(2+)-ATPase isoform 2. J. Biol. Chem. 273: 18693-18696, 1998. [PubMed: 9668038] [Full Text: https://doi.org/10.1074/jbc.273.30.18693]
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Richards, F. M., Phipps, M. E., Latif, F., Yao, M., Crossey, P. A., Foster, K., Linehan, W. M., Affara, N. A., Lerman, M. I., Zbar, B., Ferguson-Smith, M. A., Maher, E. R. Mapping the von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis. Hum. Molec. Genet. 2: 879-882, 1993. [PubMed: 8364570] [Full Text: https://doi.org/10.1093/hmg/2.7.879]
Santiago-Garcia, J., Mas-Oliva, J., Saavedra, D., Zarain-Herzberg, A. Analysis of mRNA expression and cloning of a novel plasma membrane Ca(2+)-ATPase splice variant in human heart. Molec. Cell. Biochem. 155: 173-182, 1996. [PubMed: 8700162] [Full Text: https://doi.org/10.1007/BF00229314]
Schultz, J. M., Yang, Y., Caride, A. J., Filoteo, A. G., Penheiter, A. R., Lagziel, A., Morell, R. J., Mohiddin, S. A., Fananapazir, L., Madeo, A. C., Penniston, J. T., Griffith, A. J. Modification of human hearing loss by plasma-membrane calcium pump PMCA2. New Eng. J. Med. 352: 1557-1564, 2005. Note: Erratum: New Eng. J. Med. 352: 2362 only, 2005. [PubMed: 15829536] [Full Text: https://doi.org/10.1056/NEJMoa043899]
Smits, J. J., Oostrik, J., Beynon, A. J., Kant, S. G., de Koning Gans, P. A. M., Rooteveel, L. J. C., Klein Wassink-Ruiter, J. S., Free, R. H., Maas, S. M., van de Kamp, J., Merkus, P., DOOFNL Consortium, Koole, W., Feenstra, I., Admiraal, R. J. C., Lanting, C. P., Schraders, M., Yntema, H. G., Pennings, R. J. E., Kremer, H. De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment. Hum. Genet. 138: 61-72, 2019. [PubMed: 30535804] [Full Text: https://doi.org/10.1007/s00439-018-1965-1]
Street, V. A., McKee-Johnson, J. W., Fonseca, R. C., Tempel, B. L., Noben-Trauth, K. Mutations in a plasma membrane Ca(2+)-ATPase gene cause deafness in deafwaddler mice. Nature Genet. 19: 390-394, 1998. [PubMed: 9697703] [Full Text: https://doi.org/10.1038/1284]
Wang, M. G., Yi, H., Hilfiker, H., Carafoli, E., Strehler, E. E., McBride, O. W. Localization of two genes encoding plasma membrane Ca(2+)-ATPases isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes 3p26-p25 and Xq28, respectively. Cytogenet. Cell Genet. 67: 41-45, 1994. [PubMed: 8187550] [Full Text: https://doi.org/10.1159/000133794]