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Circulation. 1995;91:2865-2867

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(Circulation. 1995;91:2865-2867.)
© 1995 American Heart Association, Inc.

Articles

Familial Hypertrophic Cardiomyopathy

Nonsense Versus Missense Mutations

Ketty Schwartz, PhD

From the INSERM UR 153, Paris, France.

Correspondence to Ketty Schwartz, INSERM UR 153, Pavillon Rambuteau, Groupe Hospitalier Pitié-Salpêtrière, 47, Boulevard de l'Hôpital, Paris Cedex 13, France.


Key Words: hypertrophic cardiomyopathy • missense mutations • nonsense mutations • myosin heavy chain • Editorials


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
During the last 5 years familial hypertrophic cardiomyopathy (FHC) has become the paradigm of inherited cardiac disorders analyzed at the molecular and genetic levels. The history of this pathology is rather unusual. Observations of myocardial diseases that can reasonably be interpreted as hypertrophic cardiomyopathy were made in the middle of the last century at the Hospital de la Salpêtrière in Paris by A. Vulpian, who called what he saw at the macroscopic level "retrecissement de l'orifice ventriculo-aortique."1 One of his pupils, H. Liouville, even predicted 1 year later that this pathology would have a great clinical impact once physicians began to pay sufficient attention to it.2 This took 1 century: it was only in the late 1950s that the unique clinical features of hypertrophic cardiomyopathy were systematically described.3 The first large pedigree was reported in 1960,4 the first disease locus in 1989,5 and the first disease gene in 1990.6 Since then, an unexpected genetic heterogeneity has been found. Four disease loci exist: CMH1 on chromosome 14q11-12,5 CMH2 on chromosome 1q3,7 CMH3 on chromosome 15q2,8 and CMH4 on chromosome 11p13-q13.9 Moreover, we have evidence that a fifth locus exists.10 Three genes have been identified within these loci, and it was a surprise to find that they encode cardiac sarcomeric proteins, ß–myosin heavy chain,6 cardiac troponin T, and {alpha}-tropomyosin.11 Indeed, none of the previous hypotheses of the pathophysiological mechanisms of the disease would have predicted that among the possible molecular bases there could be a defect in a contractile protein; nevertheless, certain forms of the disease involve mutations in sarcomeric protein genes. There is also a striking allelic heterogeneity, as 29 mutations that alter the normal amino acid (missense mutations) were found in the ß–myosin heavy chain gene, 2 in the {alpha}-tropomyosin gene, and 6 in the cardiac troponin T gene (see Reference 12 for a review). A mutation in the 5' splice donor site of intron 15 that results in aberrant truncated transcripts and a deletion of three nucleotides that do not cause a frame shift have also been found in the cardiac troponin T gene. All these mutations are dominant-negative in that they modify the activity of the remaining wild-type allele.

In this issue of Circulation, Nishi and coworkers13 report that a 16-year-old patient with FHC bears two DNA mutations in the ß–myosin heavy chain gene: a missense mutation and a nonsense mutation. The missense mutation is in exon 22 and results in the replacement at position 870 of an arginine by a histidine (Arg870His) that does not change the charge of the protein. This mutation presents the characteristics of a disease-causing mutation: it cosegregates with the disease in the proband's pedigree and in two others, and it occurs at an evolutionary conserved residue. As for the nonsense mutation, it is a C to T transition in exon 3 that results in the replacement of the arginine codon 54 (CGA) by a termination codon (TGA). The mutant allele therefore should encode a short variant of the ß–myosin heavy chain comprising only the first 53 residues of the molecule. Both the mutated and the normal sequences are present in codon 54, and thus the patient is heterozygous for the mutation. This nonsense mutation is not present in 300 unrelated patients or unrelated healthy individuals, and yet it does not present the characteristics of a disease-causing mutation because it is inherited from the unaffected mother and the unaffected grandmother of the proband. The authors suggest that it is the missense mutation that is responsible for the disease in the patient. Is the concept that a nonsense mutation in the ß–myosin heavy chain gene has no phenotypic consequences whereas a missense mutation does so surprising? Probably not. Myosin heavy chain is a multimeric protein that is part of a complex and highly organized sarcomeric structure. At a simplistic level it was hypothesized that mutations of structural proteins are frequently dominant because a mixture of normal and abnormal components disrupts the integrity of the overall structure based on a "weak links in a chain" principle.14 The mutant protein would thus act as a "poison polypeptide" that would disrupt the multimeric structure and create functional insufficiency. By contrast, loss of function mutations may have milder effects. Mutations of type I collagen in osteogenesis imperfecta, a group of inherited disorders characterized principally by brittle bones, provide the best studied example of such phenomena (see Reference 15 for a review). Collagens are produced by multiexon genes and assemble into trimeric structures that are secreted into the extracellular space where they form a complex fibrillar array. More than 50 mutations in the COL1A1 and COL1A2 genes, which encode the pro{alpha}1(I) and pro{alpha}2(I) chains of type I procollagen, produce osteogenesis imperfecta. Multiexon rearrangements are lethal if the protein product is synthesized; point mutations and single-exon deletions produce various types of phenotypes, ranging from severe to mild depending on the location and nature of the mutations, and mutations that affect the quantitative expression of the gene usually result in milder phenotypes. The assumption is that when abnormal collagen molecules are synthesized the phenotype will depend on the effect of the mutation on molecular assembly and stability, on secretion of abnormal molecules, and probably on the ability of the abnormal molecules to disturb normal fibrillogenesis. The number of abnormal collagen molecules that it takes to produce abnormal fibrils may be surprisingly small because of the constraints on molecular dimensions needed to pack molecules into fibrils. In contrast, when no abnormal type I procollagen is synthesized because of mutations that alter the amount of normal type I procollagen, the clinical expression would be mild because the structure of the fibrils would not be markedly altered. The same type of conclusion was drawn for retinitis pigmentosa, a group of hereditary retinal degenerative diseases, when more than 60 mutations in the photoreceptor protein rhodopsin were found (see Reference 16 for a review). Photoreceptors are also complex structures, and heterozygous carriers of null mutations exhibit mild phenotypes.17 The molecular consequences of nonsense mutations in general are unclear, but it is assumed that they either produce a truncated polypeptide or reduce the level and/or the stability of the mutant mRNA.18 In most cases, however, the level of protein produced from an allele containing a premature termination codon has not been determined, and it is likely that both mechanisms often operate together. However, I would not like to leave the reader with the impression that all null mutations lead to mild phenotypes. Haploinsufficiency may lead to production of insufficient quantities of protein products for the correct assembly of complexes in which stoichiometry is important for function. There are several examples of this: ribosomal protein genes whose downregulation upsets the stoichiometry of the ribosomes in Drosophila, transcription factors that often participate in competition for promoter sites and in the assembly of multimeric complexes (for example, as is suggested for Greig syndrome), and structural proteins such as ankyrin that need to be present in an exact molar ratio with spectrin.19 In hypertrophic cardiomyopathy, the same type of reasoning has been used to explain why the 5' splice donor site mutation found in the gene encoding cardiac troponin T would be at the origin of the disease. Thierfelder and coworkers11 speculate that this mutation is functionally a null allele of the gene that would produce a dominant phenotype through an imbalance in stoichiometry of thin filament components. In Drosophila, some mutations that produce null alleles of troponin T and of tropomyosin produce structurally and functionally aberrant indirect flight muscles.20 21 It is thus possible that the functional consequences of altered stoichiometry differ for troponin and myosin heavy chain, and it is certainly a fascinating hypothesis to test in the future.

From the data reported by Nishi and coworkers,13 it would be dangerous to conclude that the nonsense mutation they identified in the ß–myosin heavy chain gene is without any clinical consequence. The pedigree is very small, and the mutation has been found only in two unaffected women, 38 and 70 years of age. It could very well be that it is a nonpenetrant mutation in these women that could nevertheless have some clinical manifestation in other individuals. Marian and coworkers22 have previously observed, in a small pedigree, a 2.4 kilobase nucleotide deletion of the ß–myosin heavy chain gene including part of intron 39, exon 40 including the 3'-untranslated region and the polyadenylation signal, and part of the ß-{alpha} intergenic region. This deletion was also inherited in a mendelian fashion, but contrary to the present report by Nishi et al13 only the proband had developed clinically diagnosed hypertrophic cardiomyopathy at a very late onset (age, 59 years), and the other three family members had not developed the disease at the ages of 10, 32, and 33 years. Because the authors did not screen the gene extensively, this leaves the possibility of another mutation (maybe a missense one) in the same individuals. However, if one assumes that no other mutations exist in the pedigree described by Marian and coworkers,22 this would indeed support the idea that nonsense mutations of the myosin heavy chain gene lead to mild phenotypes. Moreover, there is mounting evidence that many point mutations in the myosin heavy chain gene are associated with low penetrance. For example, in our pedigrees with the Arg403Leu, Arg403Trp, and Asn232Ser mutations, there are 28 gene carriers, and as many as 8 of them, 21 to 51 years old, are healthy and do not present electrocardiographic or echocardiographic features of hypertrophic cardiomyopathy.23 24 From these and other findings, it is clear that other factors, including environmental differences, acquired traits (eg, differences in lifestyle, risk factors, and exercise), or modifier genes, probably modulate the phenotypic expression of the disease. The nonsense mutation found by Nishi and coworkers13 could have clinically detectable consequences in other pedigrees or even in other members of the same pedigree. In any case, it is more than likely that the nonsense mutation compounds the effects of the point mutation because the phenotype of the 16-year-old proband is of early onset and progresses rapidly.

The present findings and the nonallelic genetic heterogeneity of hypertrophic cardiomyopathy highlight the difficulties of genetic testing in sporadic cases or in very small pedigrees and the necessity for extensive screening of disease genes (at least the first 23 exons for the myosin heavy chain gene) before reaching conclusions about the consequence of a given mutation. Identification of nonpenetrant mutations and of "asymptomatically ill" individuals bearing malignant mutations raises important new clinical questions, particularly in young adults. Exchange of scientific information and careful follow-up of these selected individuals is necessary to assess whether the mutation remains a curiosity without clinical relevance (as in obligate carriers) or whether these individuals will develop the disease later on and should be given early medical management. To achieve these important goals, continuous collaboration between geneticists and cardiologists all over the world appears to be of high priority for a careful, detailed, large-scale analysis of phenotype-genotype relationships, whatever the mutation involved.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Vulpian A. Contribution à l'étude des rétrécíssements de l'orifice ventriculo-aortique. Archives de Physiologie. 1868;3:456-457.
  2. Liouville H. Rétrécissement cardiaque, sous-aortique. Gazette Médicale de Paris. 1869;12:161-163.
  3. Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J. 1958;20:1-8.
  4. Hollman A, Goodwin JF, Teare D, Renwick JW. A family with obstructive cardiomyopathy (asymmetrical hypertrophy). Br Heart J. 1960;22:449-456.
  5. Jarcho JA, McKenna W, Pare JAP, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14ql. N Engl J Med. 1989;321:1372-1378. [Abstract]
  6. Geisterfer-Lowrance AAT, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a ß cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999-1006. [Medline] [Order article via Infotrieve]
  7. Watkins H, MacRae C, Thierfelder L, Chou YH, Frenneaux M, McKenna WJ, Seidman JG, Seidman CE. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nat Genet. 1993;3:333-337. [Medline] [Order article via Infotrieve]
  8. Thierfelder L, MacRae C, Watkins H, Tomfohde J, Williams M, McKenna WJ, Bohm K, Noeske G, Schlepper M, Bowcock A, Vosberg HP, Seidman JG, Seidman CE. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc Natl Acad Sci U S A. 1993;90:6270-6274.[Abstract/Free Full Text]
  9. Carrier L, Hengstenberg C, Beckmann JS, Guicheney P, Dufour C, Bercovic J, Dausse E, Berebbi-Bertrand I, Wisnewsky C, Pulvenis D, Fetler L, Vignal A, Weissenbach J, Hillaire D, Feingold J, Bouhour JB, Hagege A, Desnos M, Isnard I, Dubourg O, Komajda M, Schwartz K. Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nat Genet. 1993;4:311-313. [Medline] [Order article via Infotrieve]
  10. Hengstenberg C, Charron P, Isnard I, Beckmann JS, Fetler L, Desnos M, Hagege A, Bouhour JB, Souriant G, Dubourg O, Schwartz K, Komajda M. Mise en évidence d'un cinquième locus impliqué dans les cardiomyopathies hypertrophiques familiales. Arch Mal Cæur. 1994;87:1655-1662.
  11. Thierfelder L, Watkins H, MacRae C, Limas R, McKenna W, Vosberg HP, Seidman JC, Seidman CE. {alpha}-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701-712. [Medline] [Order article via Infotrieve]
  12. Schwartz K, Carrier I, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation. 1995;91:532-540. [Free Full Text]
  13. Nishi H, Kimura A, Harada H, Koga, Adachi K, Matsuyama K, Koyanagi T, Imaizumi T, Toshima H, Sasazuki T. A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy. Circulation. 1995;91:2911-2915. [Abstract/Free Full Text]
  14. Wilkie AOM. The molecular basis of genetic dominance. J Med Genet. 1994;31:89-98. [Abstract/Free Full Text]
  15. Byers PH. Brittle bones fragile molecules: disorders of collagen structure and expression. Trends Genet. 1990;6:293-300. [Medline] [Order article via Infotrieve]
  16. Dietz HC, Valle D, Francomano CA, Kendzior RJ, Pyeritz RE, Cutting GR. The skipping of constitutive exons in vivo induced by nonsense mutations. Science. 1993;259:680-683. [Abstract/Free Full Text]
  17. Sanchez B, Borrego S, Chaparro P, Rueda T, Lopez F, Antinolo G. A novel null mutation in the rhodopsin gene causing late onset autosomal dominant retinitis pigmentosa. Hum Mutat. In press.
  18. McIntosh I, Hamosh A, Dietz HC. Nonsense mutations and diminished mRNA levels. Nat Genet. 1993;4:219. [Medline] [Order article via Infotrieve]
  19. Fisher E, Scambler P. Human haploinsufficiency: one for sorrow, two for joy. Nat Genet. 1994;7:5-7. [Medline] [Order article via Infotrieve]
  20. Karlik CC, Fyrberg EA. An insertion with a variably spliced Drosophila tropomyosin gene blocks accumulation of only one encoded isoform. Cell. 1985;41:57-66. [Medline] [Order article via Infotrieve]
  21. Fyrberg E, Fyrberg CC, Beall C, Saville DL. Drosophila Melanogaster troponin T mutations engender three distinct syndromes of myofibrillar abnormalities. J Mol Biol. 1990;216:657-675. [Medline] [Order article via Infotrieve]
  22. Marian AJ, Yu QT, Mares A, Hill R, Roberts R, Perryman MB. Detection of a new mutation in the ß-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy. J Clin Invest. 1992;90:2156-2165.
  23. Dausse E, Komajda M, Dubourg O, Fetler L, Dufour C, Carrier L, Wisnewski C, Bercovici J, Hengstenberg C, Al-Mahdawi S, Isnard I, Hagege A, Bouhour JB, Desnos M, Beckmann JS, Weissenbach J, Schwartz K, Guicheney P. Familial hypertrophic cardiomyopathy: microsatellite haplotyping and identification of a hot-spot for mutations in the ß-myosin heavy chain gene. J Clin Invest. 1993;92:2807-2813.
  24. Dufour C, Dausse E, Fetler L, Dubourg O, Bouhour JB, Vosberg HP, Guicheney P, Komajda M, Schwartz K. Identification of a mutation near a functional site of the ß cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy. J Mol Cell Cardiol. 1994;9:1241-1247.



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