DO: 0110309;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q22.2 | Cardiomyopathy, hypertrophic, 3 | 115196 | Autosomal dominant | 3 | TPM1 | 191010 |
A number sign (#) is used with this entry because of evidence that familial hypertrophic cardiomyopathy-3 (CMH3) is caused by heterozygous mutation in the alpha-tropomyosin gene (TPM1; 191010) on chromosome 15q22.
Familial hypertrophic cardiomyopathy-3 (CMH3) is an autosomal dominant disorder characterized by increased myocardial mass with myocyte and myofibrillar disarray (Thierfelder et al., 1994).
For a general phenotypic description and a discussion of genetic heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).
Thierfelder et al. (1993) reported affected members of 2 families of northern European origin with hypertrophic cardiomyopathy mapping to chromosome 15q22. In family MZ, the cardiomyopathy was mild, whereas in family MI, it was severe.
By linkage analysis, Thierfelder et al. (1993) identified a form of familial hypertrophic cardiomyopathy that mapped to chromosome 15q2. This was designated CMH3, CMH1 (192600) being the locus on chromosome 14 and CMH2 (115195) being the locus on chromosome 1. At least one more form of familial CMH is thought to exist because there are families that do not show linkage to any of these 3 locations. Although the gene for cardiac actin (ACTC; 102540) maps to 15q, it was excluded as a candidate gene on the basis of recombination with the CMH3 clinical phenotype (Thierfelder et al., 1993).
Schleef et al. (1993) mapped the murine alpha-tropomyosin (TPM1; 191010) gene to a region that is syntenic to human chromosome 15. Because alpha-tropomyosin is an important component of muscle thin filaments, it became a candidate gene for CMH3.
The transmission pattern of CMH3 in the families reported by Thierfelder et al. (1994) was consistent with autosomal dominant inheritance.
In affected members of 2 families with hypertrophic cardiomyopathy mapping to chromosome 15q2, Thierfelder et al. (1994) screened the candidate gene TPM1 and identified heterozygosity for 2 missense mutations, E180G in family MZ (191010.0001) and D175N in family MI (191010.0002).
Watkins et al. (1995) concluded that mutations in the TPM1 gene are a rare cause of CMH, accounting for approximately 3% of cases. These mutations, like those in the cardiac troponin T gene (TNNT2; 191045) that cause CMH2 (115195), are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group.
In a large Spanish American family with multiple members affected with hypertrophic cardiomyopathy, Karibe et al. (2001) identified a heterozygous missense mutation in the TPM1 gene (V95A; 191010.0003) that segregated with disease. The authors noted that this mutation was associated with the same mild degree of left ventricular hypertrophy as seen in some CMH1 families harboring specific mutations in MYH7 (160760.0010, 160760.0012, 160760.0001). Penetrance was estimated at 53% on the basis of an abnormal echocardiogram; however, 2 mutation carriers with normal echocardiograms and normal ECGs were only in their mid-thirties at the time of the study. Penetrance could not be accurately assessed by ECG, since 6 older mutation-negative family members had minor T-wave changes. Cumulative survival rates in this family were 73% +/- 10% at 40 years and 32% +/- 13% at 60 years.
In a 36-year-old woman of Italian extraction with cardiomyopathy, in whom a transthoracic echocardiogram was consistent with a restrictive phenotype (RCM), Caleshu et al. (2011) sequenced the exons and exon-intron boundaries of 8 known cardiomyopathy-associated genes and identified homozygosity for a missense mutation (N279H) in the TPM1 gene. The patient's cardiac catheterization pattern was consistent with a restrictive phenotype, although the dip-plateau ('square-root sign') was absent. Her first-cousin parents were each heterozygous for the mutation. Her affected 75-year-old father had been diagnosed with hypertrophic cardiomyopathy at 42 years of age, and had a history of heart failure but was currently asymptomatic. His most recent echocardiogram showed moderate asymmetric hypertrophy, mild pulmonary hypertension, mild left ventricular systolic dysfunction, and moderate biatrial enlargement, suggesting a chronic restrictive physiology. The asymptomatic 67-year-old mother underwent echocardiography after her daughter's diagnosis that revealed septal and posterior wall thicknesses that were at the upper limit of normal, with mild biatrial enlargement with normal systolic function and no significant evidence of restrictive physiology.
Muthuchamy et al. (1999) generated a transgenic mouse model of CMH3. They employed site-directed mutagenesis to convert the wildtype murine GAC sequence at codon 175 to AAC, thus introducing the missense mutation asp175 to asn (191010.0002). S1 nuclease mapping and Western blot analysis demonstrated an increase in mutant alpha-tropomyosin mRNA and protein and a concomitant decrease in endogenous mRNA and protein. In vivo studies demonstrated a significant impairment of left ventricular systolic function, and in vitro analysis of papillary muscle fibers showed a decrease in contractile function. Histologic examination of transgenic cardiac tissue showed patchy ventricular myocyte disarray and hypertrophy. This mild and patchy phenotype was in agreement with the clinical features of patients with the asp175-to-asn mutation (Coviello et al., 1997).
Caleshu, C., Sakhuja, R., Nussbaum, R. L., Schiller, N. B., Ursell, P. C., Eng, C., De Marco, T., McGlothlin, D., Burchard, E. G., Rame, J. E. Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy. Am. J. Med. Genet. 155A: 2229-2235, 2011. [PubMed: 21823217] [Full Text: https://doi.org/10.1002/ajmg.a.34097]
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Muthuchamy, M., Pieples, K., Rethinasamy, P., Hoit, B., Grupp, I. L., Boivin, G. P., Wolska, B., Evans, C., Solaro, R. J., Wieczorek, D. F. Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. Circ. Res. 85: 47-56, 1999. [PubMed: 10400910] [Full Text: https://doi.org/10.1161/01.res.85.1.47]
Schleef, M., Werner, K., Satzger, U., Kaupmann, K., Jokusch, H. Chromosomal location and genomic cloning of the mouse alpha-tropomyosin gene Tpm-1. Genomics 17: 519-521, 1993. [PubMed: 8406508] [Full Text: https://doi.org/10.1006/geno.1993.1361]
Thierfelder, L., MacRae, C., Watkins, H., Tomfohrde, J., Williams, M., McKenna, W., Bohm, K., Noeske, G., Schlepper, M., Bowcock, A., Vosberg, H.-P., Seidman, J. G., Seidman, C. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc. Nat. Acad. Sci. 90: 6270-6274, 1993. [PubMed: 8327508] [Full Text: https://doi.org/10.1073/pnas.90.13.6270]
Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77: 701-712, 1994. [PubMed: 8205619] [Full Text: https://doi.org/10.1016/0092-8674(94)90054-x]
Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. New Eng. J. Med. 332: 1058-1064, 1995. [PubMed: 7898523] [Full Text: https://doi.org/10.1056/NEJM199504203321603]