Alternative titles; symbols
HGNC Approved Gene Symbol: TMPO
Cytogenetic location: 12q23.1 Genomic coordinates (GRCh38) : 12:98,515,573-98,550,351 (from NCBI)
Harris et al. (1995) determined that a single TMPO gene encodes 3 thymopoietins: alpha (75 kD), beta (51 kD), and gamma (39 kD). TMPO-alpha is present diffusely throughout the nucleus, whereas TMPOs beta and gamma are localized to the nuclear membrane. Harris et al. (1995) cloned the TMPO gene and found that the 3 isoforms are produced by alternative mRNA splicing. Exon 4, which is spliced into TMPO-alpha mRNA, contains sequences that encode a putative basic nuclear localization motif. Exon 8, which is spliced into TMPO-beta and TMPO-gamma mRNAs, encodes a hydrophobic putative membrane-spanning domain that is thought to target these 2 gene products to the nuclear membrane. Harris et al. (1995) pointed out that TMPO-beta appears to be the human homolog of the rat protein Lap2, which is thought to play an important role in the regulation of nuclear architecture by binding lamin B1 and chromosomes in a manner regulated by phosphorylation during mitosis.
Berger et al. (1996) cloned and characterized the mouse Tmpo gene. Because of their finding of novel alternatively spliced mouse transcripts, they reanalyzed the human TMPO gene. The human beta-specific domain was found to be encoded by 3 exons, designated 6a, 6b, and 6c, and not by a single exon as described previously. Berger et al. (1996) discussed the possible involvement of the family of thymopoietins in nuclear architecture and cell cycle control.
Harris et al. (1995) determined that the TMPO gene contains 8 exons spread over approximately 35 kb.
Harris et al. (1995) mapped the TMPO gene to chromosome 12q22 by fluorescence in situ hybridization. Berger et al. (1996) mapped the mouse Tmpo gene to the central region of chromosome 10.
Exclusion Studies
Gupta et al. (2010) analyzed the TMPO gene in endomyocardial biopsy samples from 25 unrelated patients with dilated cardiomyopathy but did not find any mutations.
Naetar et al. (2008) noted that, unlike other Lap2 isoforms, which are integral proteins of the inner nuclear membrane, Lap2-alpha localizes to the nucleoplasm, where it interacts with A-type lamins and Rb (RB1; 614041) and affects gene expression. Naetar et al. (2008) generated mice specifically lacking Lap2-alpha and found that they were viable and indistinguishable from wildtype. Lap2-alpha -/- muscle, liver, and heart appeared normal. In contrast, plantar paw epidermis, but not paw dorsum and back skin, was thicker than wildtype. Thickening was due to stress-induced hyperproliferation linked to elevated Rb phosphorylation. Lap2-alpha -/- mice also showed increased numbers of erythroid progenitors in spleen and bone marrow, as well as elevated hematocrit. Lap2-alpha -/- fibroblasts did not have altered A-type lamin expression, but A-type lamin showed relocalization from the nucleoplasm to the nuclear periphery. Naetar et al. (2008) concluded that nucleoplasmic Lap2-alpha and A-type lamins regulate early progenitor cell proliferation in regenerative tissues.
By echocardiography in Lap2-alpha-null mice at age 10 weeks, Gotic et al. (2010) observed ventricular systolic dysfunction characterized by significantly decreased left ventricular fractional shortening (FS%) and ejection fraction in male mice. The mice also had enlarged left atria suggestive of left ventricular and left atrial volume overload. The FS% and ejection fraction remained depressed in old Lap2-alpha-null mice (aged 10 to 12 months), suggesting that the functional defect was not progressive. Older mice also exhibited sporadic subendocardial fibrosis of the left ventricle. Cardiac parameters in female mice were comparable to wildtype at both ages. Analysis of markers of myocardial remodeling showed that loss of Lap2-alpha caused deregulated expression patterns of the major cardiac transcription factors GATA4 (600576) and MEF2C (600662) as well as some of their downstream targets. Lap2-alpha-deficient hearts showed a blunted response to chronic stimulation with the beta-adrenergic agonist ISO, pointing to the existence of compensatory pathways activated in response to changes in cardiac function in the Lap2-alpha-null mice.
This variant, formerly designated CARDIOMYOPATHY, DILATED, 1T, has been reclassified based on a review of the ExAC database (February 6, 2017) by Hamosh (2017).
Taylor et al. (2005) identified LAP2 as a candidate gene for CMD on the basis of its association with lamin A/C (150330), which is mutated in a form of CMD (CMD1A; 115200). They screened 113 individuals with dilated cardiomyopathy from 88 families for mutation in the LAP2 gene and identified a heterozygous 2068C-T transition in the TMPO gene, predicting an arg690-to-cys (R690C) substitution in the C-terminal domain of the LAP2-alpha protein, in 2 brothers with severe CMD. The older brother first developed cardiac symptoms at age 31 and was diagnosed with CMD at age 33 with a left ventricular ejection fraction of 10%. His brother had symptoms at the age of 22 and was diagnosed at age 24 with an ejection fraction of 32%. The brothers' mother and maternal grandmother reportedly had idiopathic CMD and heart failure, suggesting an autosomal dominant mode of inheritance. The mutation was not found in 300 control chromosomes or in 222 chromosomes of other patients with CMD. Immunofluorescence microscopy in transfected HeLa cells showed localization of mutant LAP2-alpha that was indistinguishable from that of endogenous wildtype protein, indicating that the mutation did not severely impair LAP2-alpha structure and assembly; in addition, expression of mutant LAP2-alpha did not affect distribution of endogenous LAP2-alpha. However, in vitro binding studies using the prelamin A tail (see 150330) demonstrated that the relative amount of bound mutated LAP2-alpha was reduced by 50 to 75% compared to wildtype protein, indicating that the in vitro interaction of R690C mutant LAP2-alpha with the prelamin A tail was significantly reduced compared to wildtype.
Hamosh (2017) noted that the R690C variant in the ExAC database (February 6, 2017) had a high allele frequency (1.5%) and was found in 141 homozygotes, suggesting that it is not pathogenic.
Berger, R., Theodor, L., Shoham, J., Gokkel, E., Brok-Simoni, F., Avraham, K. B., Copeland, N. G., Jenkins, N. A., Rechavi, G., Simon, A. J. The characterization and localization of the mouse thymopoietin/lamina-associated polypeptide 2 gene and its alternatively spliced products. Genome Res. 6: 361-370, 1996. [PubMed: 8743987] [Full Text: https://doi.org/10.1101/gr.6.5.361]
Gotic, I., Leschnik, M., Kolm, U., Markovic, M., Haubner, B. J., Biadasiewicz, K., Metzler, B., Stewart, C. L., Foisner, R. Lamina-associated polypeptide 2-alpha loss impairs heart function and stress response in mice. Circ. Res. 106: 346-353, 2010. [PubMed: 19926876] [Full Text: https://doi.org/10.1161/CIRCRESAHA.109.205724]
Gupta, P., Bilinska, Z. T., Sylvius, N., Boudreau, E., Veinot, J. P., Labib, S., Bolongo, P. M., Hamza, A., Jackson, T., Ploski, R., Walski, M., Grzybowski, J., Walczak, E., Religa, G., Fidzianska, A., Tesson, F. Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption. Basic Res. Cardiol. 105: 365-377, 2010. [PubMed: 20127487] [Full Text: https://doi.org/10.1007/s00395-010-0085-4]
Hamosh, A. Personal Communication. Baltimore, Md. February 6, 2017.
Harris, C. A., Andryuk, P. J., Cline, S. W., Mathew, S., Siekierka, J. J., Goldstein, G. Structure and mapping of the human thymopoietin (TMPO) gene and relationship of human TMPO beta to rat lamin-associated polypeptide 2. Genomics 28: 198-205, 1995. [PubMed: 8530026] [Full Text: https://doi.org/10.1006/geno.1995.1131]
Naetar, N., Korbei, B., Kozlov, S., Kerenyi, M. A., Dorner, D., Kral, R., Gotic, I., Fuchs, P., Cohen, T. V., Bittner, R., Stewart, C. L., Foisner, R. Loss of nucleoplasmic LAP2-alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation. Nature Cell Biol. 10: 1341-1348, 2008. [PubMed: 18849980] [Full Text: https://doi.org/10.1038/ncb1793]
Taylor, M. R. G., Slavov, D., Gajewski, A., Vlcek, S., Ku, L., Fain, P. R., Carniel, E., De Lenarda, A., Sinagra, G., Boucek, M. M., Cavanaugh, J., Graw, S. L., and 9 others. Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy. Hum. Mutat. 26: 566-574, 2005. [PubMed: 16247757] [Full Text: https://doi.org/10.1002/humu.20250]