Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRF
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38): 1:43,522,051-43,623,666 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.2 | ?Breasts and/or nipples, aplasia or hypoplasia of, 2 | 616001 | Autosomal recessive | 3 |
The LAR (PTPRF) gene encodes a membrane protein that has a cytoplasmic domain with homology to protein-tyrosine phosphatase 1B (176885) and an extracellular domain homologous to the neural cellular adhesion molecule NCAM (116930).
The human LAR molecule closely resembles cell adhesion molecules, which suggests that it may be involved in the regulation of phosphotyrosine levels through cell-cell or cell-matrix interactions. As a first step toward site-directed mutagenesis studies of LAR function, Schaapveld et al. (1995) characterized the mouse Ptprf gene.
Schaapveld et al. (1995) found that the cytoplasmic region of the mouse Ptprf gene is encoded by 11 exons that span only 4.5 kb of genomic DNA. Compared to the known exon-intron structures of other mammalian receptor-like protein tyrosine phosphatase genes such as Ptpra (encoding LRP; 176884) and Ptprc (coding for Ly-5; 151460), the portion of the Ptprf gene encoding the cytoplasmic region of murine LAR contained not only smaller, but also fewer introns.
O'Grady et al. (1994) demonstrated that the human LAR gene is composed of 33 exons spanning over 85 kb. Exon 2 encodes the signal sequence and the first 4 amino acids in the mature LAR protein. The 3 immunoglobulin-like domains are encoded by exons 3 to 7, and the 8 fibronectin type III (FN-III) domains by exons 8 to 17. Exons 18 to 22 encode the juxtamembrane and transmembrane domains, and exons 23 to 33 encode the 2 conserved tyrosine phosphatase domains and the entire 3-prime untranslated region. Alternative splicing of LAR mRNA was revealed by RT-PCR analysis.
Ahmad and Goldstein (1997) reported that LAR is synthesized as an approximately 200-kD protein that is proteolytically processed into 2 noncovalently associated subunits: a 150-kD extracellular (E) subunit that contains the cell adhesion molecule domains, and an 85-kD phosphatase (P) subunit that contains extracellular, transmembrane, and cytoplasmic domains. Ahmad and Goldstein (1997) carried out several studies to elucidate the relationship between LAR and the insulin signaling pathway. They demonstrated that anti-LAR antibodies inhibit the activity of overexpressed human insulin receptor (147670) in Chinese hamster ovary cells. Immunoprecipitation of LAR from cell lysates and immunoblotting with antibody to the insulin receptor (or vice versa) showed a physical association between LAR and the insulin receptor. In insulin-stimulated rat liver cells, LAR was temporally internalized into a similar endosomal compartment as the insulin receptor. Ahmad and Goldstein (1997) concluded that LAR acts as a protein-tyrosine phosphatase that negatively regulates the insulin signaling pathway.
Nam et al. (1999) determined the crystal structure of the tandem D1 and D2 domains of the human LAR.
Most receptor-like transmembrane protein-tyrosine phosphatases (PTPases) such as CD45 and the PTPRF molecule have 2 tandemly repeated PTPase domains in the cytoplasmic segment. Tsujikawa et al. (2001) examined the function of each PTPase domain of PTPRF in vivo using a potential physiologic substrate, insulin receptor, and PTPRF mutant proteins. PTPRF associated with and preferentially dephosphorylated the insulin receptor that was tyrosine phosphorylated by insulin stimulation. Its association was mediated by PTPase domain 2, because the cys1813-to-ser mutation in domain 2 resulted in weakening of the association. The cys1522-to-ser mutant protein, which is defective in the PTPRF PTPase domain 1 catalytic site, was tightly associated with tyrosine-phosphorylated insulin receptor, but failed to dephosphorylate it, indicating that PTPRF PTPase domain 1 is critical for dephosphorylation of tyrosine-phosphorylated insulin receptor. The authors concluded that each domain of PTPRF plays distinct functional roles through phosphorylation and dephosphorylation in vivo.
By in situ hybridization, Disteche et al. (1989) mapped the LAR gene to 1p34-p32. The related leukocyte common antigen (LCA, also known as CD45; 151460) also maps to chromosome 1. By in situ hybridization, Jirik et al. (1992) mapped LAR, a putative tumor suppressor gene, to 1p32, a region frequently deleted in human neuroblastoma and pheochromocytoma. Harder et al. (1995) found that coamplification of the PTPRF gene and the MYCL1 gene (164850) in a small cell lung cancer line supported close linkage of the 2 genes.
By fluorescence in situ hybridization, Schaapveld et al. (1995) mapped the Ptprf gene to mouse chromosome 4.
Ausavarat et al. (2011) reported an 18-year-old Thai woman with bilateral amastia, ectodermal dysplasia, unilateral renal agenesis, and mildly dysmorphic facial features who had a reciprocal balanced translocation, 46,XX,t(1;20)(p34.1;q13.13). Further analysis showed that the translocation disrupted the PTPRF gene between intron 7 and intron 11. Her mother and sisters had the same translocation, but were unaffected. The patient's PTPRF RNA and protein levels were severely deficient compared to those of her mother, a sister, and a control. Sequencing of the coding and promoter regions of the PTPRF gene did not reveal any pathogenic mutations; likewise, no aberrant splicing was seen on reverse transcribed PCR. The sisters were shown to have inherited a different paternal chromosome 1 than that of the patient, suggesting that the father, who was deceased, might have transmitted an unidentified pathogenic variant in the PTPRF gene to the proband.
Aplasia or Hypoplasia of Breast and/or Nipples 2
In a consanguineous pedigree of Israeli Arab origin with unilateral or bilateral absence of breast tissue and/or nipples mapping to chromosome 1p34 (BNAH2; 616001), Borck et al. (2014) sequenced 3 candidate genes and identified homozygosity for a 2-bp deletion in the PTPRF gene (179590.0001) that segregated with disease in the family and was not found in controls.
Somatic Mutations
Wang et al. (2004) performed mutation analysis of the tyrosine phosphatase gene superfamily in human cancers and identified 83 somatic mutations in 6 protein-tyrosine phosphatases (PTPRF; PTPRG, 176886; PTPRT, 608712; PTPN3, 176877; PTPN13, 600267; and PTPN14, 603155), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice site alterations predicted to result in truncated proteins lacking phosphatase activity. Wang et al. (2004) biochemically examined 5 missense mutations in PTPRT, the most commonly altered protein-tyrosine phosphatase, and found that they reduced phosphatase activity. Expression of wildtype but not a mutant PTPRT in human cancer cells inhibited cell growth. Wang et al. (2004) concluded that their observations suggested that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
Schaapveld et al. (1997) used gene targeting in mouse embryonic stem cells to generate mice lacking sequences encoding both Lar phosphatase domains. Homozygous mutant mice developed and grew normally. However, mammary glands of homozygous Lar-deficient females were incapable of delivering milk due to an impaired terminal differentiation of alveoli at late pregnancy. The authors concluded that LAR-mediated signaling may play an important role in mammary gland development and function.
Uetani et al. (2009) obtained late Ptprs (601576)/Ptprf double-knockout mouse embryos at the expected mendelian ratio, but none survived to 4 weeks of age, likely due to lethality of Ptprs knockout. At embryonic day 18.5, double-knockout embryos showed severe craniofacial defects, including exencephaly, micrognathia, and failure of eyelid closure. Additional malformation of the eye included hyperplastic inner nuclear layers, persistence of prominent hyaloid arteries, abnormal retrolental tissues, and disorganized neural retina. Double-knockout embryos also showed striking abnormalities of the urinary tract, such as hydroureters, hydronephrosis, duplicated ureter/renal systems, and ureterocele. Absence of Ptprs and Ptprf activity prevented normal execution of the apoptotic program necessary for regression of the common nephric duct during development, resulting in inappropriate tissue survival and delayed distal ureter maturation. In cell culture, Ptprs bound and negatively regulated the phosphorylation and signaling of the Ret receptor tyrosine kinase (164761), whereas Ptprs-induced apoptosis was inhibited by Ret expression. Uetani et al. (2009) concluded that ureter positioning is controlled by the opposing actions of RET and LAR family phosphatases regulating apoptosis-mediated tissue morphogenesis.
In a sister and brother and their first cousin from a consanguineous pedigree of Israeli Arab origin with unilateral or bilateral aplasia or hypoplasia of breast tissue and/or nipples (BNAH2; 616001), Borck et al. (2014) identified homozygosity for a 2-bp deletion (c.1847_1848delTG) in exon 12 of the PTPRF gene, causing a frameshift predicted to result in a premature stop codon (Val616GlufsTer49). The sibs' unaffected parents were heterozygous for the mutation, which was not found in the dbSNP (build 137) database or in approximately 6,400 European and African American individuals sequenced at this position in the NHLBI Exome Sequencing Project database.
Ahmad, F., Goldstein, B. J. Functional association between the insulin receptor and the transmembrane protein-tyrosine phosphatase LAR in intact cells. J. Biol. Chem. 272: 448-457, 1997. [PubMed: 8995282]
Ausavarat, S., Tongkobpetch, S., Praphanphoj, V., Mahatumarat, C., Rojvachiranonda, N., Snabboon, T., Markello, T. C., Gahl, W. A., Suphapeetiporn, K., Shotelersuk, V. PTPRF is disrupted in a patient with syndromic amastia. BMC Med. Genet. 12: 46, 2011. [PubMed: 21453473] [Full Text: https://doi.org/10.1186/1471-2350-12-46]
Borck, G., de Vries, L., Wu, H.-J., Smirin-Yosef, P., Nurnberg, G., Lagovsky, I., Ishida, L. H., Thierry, P., Wieczorek, D., Nurnberg, P., Foley, J., Kubisch, C., Basel-Vanagaite, L. Homozygous truncating PTPRF mutation causes athelia. Hum. Genet. 133: 1041-1047, 2014. [PubMed: 24781087] [Full Text: https://doi.org/10.1007/s00439-014-1445-1]
Disteche, C. M., Adler, D. A., Tedder, T. F., Saito, H. Mapping of the genes for LYAM1, a new lymphocyte adhesion molecule, and for LAR, a new receptor-linked protein tyrosine phosphatase, to human chromosome 1. (Abstract) Cytogenet. Cell Genet. 51: 990 only, 1989.
Harder, K. W., Saw, J., Miki, N., Jirik, F. Coexisting amplifications of the chromosome 1p32 genes (PTPRF and MYCL1) encoding protein tyrosine phosphatase LAR and L-myc in a small cell lung cancer line. Genomics 27: 552-553, 1995. [PubMed: 7558042] [Full Text: https://doi.org/10.1006/geno.1995.1092]
Jirik, F. R., Harder, K. W., Melhado, I. G., Anderson, L. L., Duncan, A. M. V. The gene for leukocyte antigen-related tyrosine phosphatase (LAR) is localized to human chromosome 1p32, a region frequently deleted in tumors of neuroectodermal origin. Cytogenet. Cell Genet. 61: 266-268, 1992. [PubMed: 1486801] [Full Text: https://doi.org/10.1159/000133418]
Nam, H.-J., Poy, F., Krueger, N. X., Saito, H., Frederick, C. A. Crystal structure of the tandem phosphatase domains of RPTP LAR. Cell 97: 449-457, 1999. [PubMed: 10338209] [Full Text: https://doi.org/10.1016/s0092-8674(00)80755-2]
O'Grady, P., Krueger, N. X., Streuli, M., Saito, H. Genomic organization of the human LAR protein tyrosine phosphatase gene and alternative splicing in the extracellular fibronectin type-III domains. J. Biol. Chem. 269: 25193-25199, 1994. [PubMed: 7929208]
Schaapveld, R. Q. J., van den Maagdenberg, A. M. J. M., Schepens, J. T. G., Olde Weghuis, D., Geurts van Kessel, A., Wieringa, B., Hendriks, W. J. A. J. The mouse gene Ptprf encoding the leukocyte common antigen-related molecule LAR: cloning, characterization, and chromosomal localization. Genomics 27: 124-130, 1995. [PubMed: 7665159] [Full Text: https://doi.org/10.1006/geno.1995.1014]
Schaapveld, R. Q., Schepens, J. T., Robinson, G. W., Attema, J., Oerlemans, F. T., Fransen, J. A., Streuli, M., Wieringa, B., Hennighausen, L., Hendriks, W. J. Impaired mammary gland development and function in mice lacking LAR receptor-like tyrosine phosphatase activity. Dev. Biol. 188: 134-146, 1997. [PubMed: 9245518] [Full Text: https://doi.org/10.1006/dbio.1997.8630]
Tsujikawa, K., Kawakami, N., Uchino, Y., Ichijo, T., Furukawa, T., Saito, H., Yamamoto, H. Distinct functions of the two protein tyrosine phosphatase domains of LAR (leukocyte common antigen-related) on tyrosine dephosphorylation of insulin receptor. Molec. Endocr. 15: 271-280, 2001. [PubMed: 11158333] [Full Text: https://doi.org/10.1210/mend.15.2.0592]
Uetani, N., Bertozzi, K., Chagnon, M. J., Hendriks, W., Tremblay, M. L., Bouchard, M. Maturation of ureter-bladder connection in mice is controlled by LAR family receptor protein tyrosine phosphatases. J. Clin. Invest. 119: 924-935, 2009. [PubMed: 19273906] [Full Text: https://doi.org/10.1172/JCI37196]
Wang, Z., Shen, D., Parsons, D. W., Bardelli, A., Sager, J., Szabo, S., Ptak, J., Silliman, N., Peters, B. A., van der Heijden, M. S., Parmigiani, G., Yan, H., Wang, T.-L., Riggins, G., Powell, S. M., Willson, J. K. V., Markowitz, S., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304: 1164-1166, 2004. [PubMed: 15155950] [Full Text: https://doi.org/10.1126/science.1096096]