Alternative titles; symbols
HGNC Approved Gene Symbol: PPP1R12A
Cytogenetic location: 12q21.2-q21.31 Genomic coordinates (GRCh38) : 12:79,773,563-79,935,460 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.2-q21.31 | Genitourinary and/or/brain malformation syndrome | 618820 | Autosomal dominant | 3 |
PPP1R12A is a regulatory subunit of myosin light chain phosphatase, which plays an essential role in smooth muscle contraction (Qiao et al., 2014).
Using the rat Mypt1 cDNA as probe, Takahashi et al. (1997) cloned a 4,855-bp cDNA for a human gene they symbolized MYPT1. Sequencing analysis showed that human MYPT1 contains 1,030 amino acids with a calculated molecular mass of approximately 115 kD.
By fluorescence in situ hybridization, Kimura et al. (1996) mapped the MYPT1 gene to chromosome 12q15-q21.2. By radiation hybrid analysis, they showed that MYPT1 is located close to a highly polymorphic marker that lies between D12S350 and D12S106.
Crystal Structure
Terrak et al. (2004) determined the crystal structure at 2.7-angstrom resolution of the complex between protein phosphatase-1 (PP1; see 176875) and a 34-kD N-terminal domain of the myosin phosphatase targeting subunit MYPT1. MYPT1 is the protein that regulates PP1 function in smooth muscle relaxation. Structural elements amino- and carboxy-terminal to the RVXF motif of MYPT1 are positioned in a way that leads to a pronounced reshaping of the catalytic cleft of PP1, contributing to the increased myosin specificity of this complex. Terrak et al. (2004) concluded that the structure has general implications for the control of PP1 activity by other regulatory subunits.
Kimura et al. (1996) demonstrated that myosin phosphatase regulates the interaction of actin (see 102540) and myosin (see 160710) downstream of the guanosine triphosphatase Rho. Rho appears to inhibit myosin phosphatase through the action of Rho-kinase.
Jin et al. (2006) identified MYPT1 as the enzyme that activates the tumor suppressor function of merlin, encoded by the NF2 gene (607379). The cellular MYPT1-PP1-delta (600590)-specific inhibitor CPI17 (608153) caused a loss of merlin function characterized by merlin phosphorylation, Ras activation, and transformation. Constitutively active merlin containing the mutation S518A reversed CPI17-induced transformation, showing that merlin is the decisive substrate of MYPT1-PP1-delta in tumor suppression. In addition Jin et al. (2006) showed that CPI17 levels are raised in several human tumor cell lines and that the downregulation of CPI17 induces merlin dephosphorylation, inhibits Ras activation, and abolishes the transformed phenotype. Jin et al. (2006) concluded that MYPT1 and its substrate merlin are part of a previously undescribed tumor suppressor cascade that can be hindered in 2 ways, by mutation of the NF2 gene and by upregulation of the oncoprotein CPI17.
In 12 unrelated patients with genitourinary and/or brain malformations (GUBS; 618820), Hughes et al. (2020) identified heterozygosity for de novo premature termination codon (PTC) variants in the PPP1R12A gene (see, e.g., 602021.0001-602021.0003). The authors noted that the patients exhibited a broad spectrum of clinical manifestations, and that the PPP1R12A variants occurred across multiple exons and 1 intron, with no clear genotype-phenotype correlation observed with specific variants.
Qiao et al. (2014) generated conditional knockout mice lacking Mypt1 specifically in smooth muscle cells. Western blot analysis confirmed that mesenteric, femoral, and aortic smooth muscle tissues from mutant mice contained only trace or undetectable amounts of Mypt1 protein. Mypt1 deletion resulted in enhanced myosin regulatory light chain phosphorylation and contractility of vascular smooth muscle in response to a variety of vasoactive stimuli. Mutant mice exhibited permanent hypertension without changes in vascular structure, suggesting that the hypertension may have resulted from enhanced arterial contractile responses. Qiao et al. (2014) concluded that MYPT1 modulates vascular smooth muscle contractility and contributes to blood pressure maintenance in vivo.
In a 6-year-old 46,XY boy (patient 6) with genitourinary and brain malformations (GUBS; 618820), Hughes et al. (2020) identified heterozygosity for a de novo c.1510C-T transition (c.1510C-T, NM_002480.3) in the PPP1R12A gene, resulting in an arg504-to-ter (R504X) substitution. The patient had glandular hypospadias and chordee; encephalocele noted on prenatal ultrasound was repaired shortly after birth. Brain MRI showed dysgenesis of the corpus callosum, absent septum pellucidum, Chiari malformation, cortical dysplasia/polymicrogyria, and gray matter heterotopia. Examination revealed global developmental delay, intellectual disability with limited speech, autistic features, appendicular hypotonia with foot pronation, and unsteady gait. He also exhibited minor facial dysmorphisms such as low-set ears and micrognathia, and had short stature, patent ductus arteriosus, and ophthalmologic abnormalities including strabismus, astigmatism, and hyperopia.
In a 30-year-old 46,XY female (patient 11) with genitourinary malformations and developmental delay (GUBS; 618820), Hughes et al. (2020) identified heterozygosity for a de novo 1-bp deletion (c.1189delA, NM_002480.3) in the PPP1R12A gene, causing a frameshift predicted to result in a premature termination codon (Thr397HisfsTer42). She exhibited gonadal dysgenesis, including streak gonads, rudimentary fallopian tubes, and urogenital sinus with no uterus. Other features included alopecia totalis, obesity, acanthosis nigricans, and developmental delay. Brain MRI was unremarkable.
In a 15-year-old 46,XX girl (patient 1) with brain malformations (GUBS; 618820), Hughes et al. (2020) identified heterozygosity for a de novo 2-bp deletion (c.2033_2034delCT, NM_002480.3), causing a frameshift predicted to result in a premature termination codon (ser678 to ter; S678X). The patient had intellectual disability, attention-deficit/hyperactivity disorder, and seizures; brain MRI showed syntelencephaly/middle interhemispheric variant of holoprosencephaly, polymicrogyria, and Chiari I malformation. Genitourinary evaluation was not performed.
Hughes, J. J., Alkhunaizi, E., Kruszka, P., Pyle, L. C., Grange, D. K., Berger, S. I., Payne, K. K., Masser-Frye, D., Hu, T., CHristie, M. R., Clegg, N. J., Everson, J. L., and 18 others. Loss-of-function variants in PPP1R12A: from isolated sex reversal to holoprosencephaly spectrum and urogenital anomalies. Am. J. Hum. Genet. 106: 121-128, 2020. [PubMed: 31883643] [Full Text: https://doi.org/10.1016/j.ajhg.2019.12.004]
Jin, H., Sperka, T., Herrlich, P., Morrison, H. Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature 442: 576-579, 2006. [PubMed: 16885985] [Full Text: https://doi.org/10.1038/nature04856]
Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori, B., Feng, J., Nakano, T., Okawa, K., Iwamatsu, A., Kaibuchi, K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273: 245-248, 1996. [PubMed: 8662509] [Full Text: https://doi.org/10.1126/science.273.5272.245]
Qiao, Y.-N., He, W.-Q., Chen, C.-P., Zhang, C.-H., Zhao, W., Wang, P., Zhang, L., Wu, Y.-Z., Yang, X., Peng, Y.-J., Gao, J.-M., Kamm, K. E., Stull, J. T., Zhu, M.-S. Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure. J. Biol. Chem. 289: 22512-22523, 2014. [PubMed: 24951589] [Full Text: https://doi.org/10.1074/jbc.M113.525444]
Takahashi, N., Ito, M., Tanaka, J., Nakano, T., Kaibuchi, K., Odai, H., Takemura, K. Localization of the gene coding for myosin phosphatase, target subunit 1 (MYPT1) to human chromosome 12q15-q21. Genomics 44: 150-152, 1997. [PubMed: 9286714] [Full Text: https://doi.org/10.1006/geno.1997.4859]
Terrak, M., Kerff, F., Langsetmo, K., Tao, T., Dominguez, R. Structural basis of protein phosphatase 1 regulation. Nature 429: 780-784, 2004. [PubMed: 15164081] [Full Text: https://doi.org/10.1038/nature02582]