Unexpectedly low mutation rates in beta‐myosin heavy chain and cardiac myosin binding protein genes in italian patients with hypertrophic cardiomyopathy

Roncarati, Roberta; Latronico, Michael V.G.; Musumeci, Beatrice; Aurino, S.; Torella, Annalaura; Bang, Marie Louise; Jotti, Gloria Saccani; Puca, Annibale Alessandro; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

doi:10.1002/jcp.22636

Cited by 16 publications

(8 citation statements)

References 42 publications

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“…In contrast to other studies, genetic results from this study show an unusually low number of mutations in the MYH 7 gene in the tested regions ( 14 , 27 - 29 ). Only Roncarati et al have recently reported a low frequency of mutations in the MYH 7 gene in a large cohort of Italian patients with HCM ( 30 ).…”

Section: Discussioncontrasting

confidence: 99%

Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein

Capek

Vondrášek²,

Škvor³

et al. 2011

Croat Med J

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AimTo analyze the genesis of hypertrophic cardiomyopathy on a large cohort of patients from molecular genetics point of view and perform the functional analysis of the 3D molecular model of defective myosin-7 protein in silico.MethodsThe study enrolled 153 patients with diagnosed hypertrophic cardiomyopathy from different parts of the Czech Republic. DNA samples were analyzed for mutations in exons 21 and 22 of the MYH7 gene, which have been associated with high mutation clustering. The 3D model of human myosin-7 was built using the x-ray structure of nucleotide-free scallop myosin S1 as the structural template. We performed de novo structure prediction of mutant and wild type peptides spanning the 769-788 amino acids region of the myosin-7 protein.ResultsThe Arg870His and Asp778Val amino acid alterations were found in 2 unrelated patients with a severe form of hypertrophic cardiomyopathy. The Asp778Val variation was chosen for subsequent 3D molecular modeling in silico. The mutation of the Asp by Val not only changes the character of the interaction pattern with other amino acids or ions but Val, being a small hydrophobic amino acid, can also completely change the stability of the region.ConclusionMutation location in the MYH7 gene and changes in amino acid composition may have a crucial negative impact on the outcome of the disease in patients with hypertrophic cardiomyopathy. In addition, a mutation that changes the charge of the amino acid is more likely to affect protein function than a conservative mutation.

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Section: Discussioncontrasting

confidence: 99%

Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein

Capek

Vondrášek²,

Škvor³

et al. 2011

Croat Med J

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“…We found 24 sarcomeric missense rare variants, accounting for 4.4% of tested families in MYH6 (3/69; c.2489 C>T, p.P830L; c.3010 G>T, p.A1004S; 4369 G>A, p.E1457K), 4.4% in MYH7 (3/67; c.2945 T>C, p.M982T; c.4300 C>T, p.R1434C; c.4498 C>T, p.R1500W), 1.8% in MYBPC3 (3/168; c.649 A>G, p.S217G; c.1373 G>A, p.R458H; c.2870 C>G, p.T957S), 4.4% in TNNT2 (3/68; c.391 C>T, p.R131W, and c.517 C>T, p.R173W the latter found in two nuclear families) and 8.8% in TTN (13/147; c.6247delG, p.R2883fs; c.91043delA, p.N30348fs; c.49077G>A, p.W16359X; c.51883G>A, p.R17295X; c.52408C>T, p.R17470X; c.53347G>T, p.E17783X; c.56953C>T, p.R18985X; c.79896G>A, p.W26632X; c.81046A>T, p.K27016X; c.87953G>A, p.w29318X; c.88242C>T, p.R29415X; c.50346+3A>G, p.K16782; c.53145_53146insG, p.E17715fs). All rare variants were novel and suspected of being pathogenic or had previously been reported as mutations in DCM or HCM) and were absent in control samples. The characteristics of the rare variants are shown in Table S1 and the pedigrees of familial DCM cases in Figures S1–S3.…”

Section: Resultsmentioning

confidence: 94%

Poor Prognosis of Rare Sarcomeric Gene Variants in Patients with Dilated Cardiomyopathy

Merlo

Sinagra

Carniel³

et al. 2013

Clinical Translational Sci

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Background In dilated cardiomyopathy (DCM), the clinical and prognostic implications of rare variants in sarcomeric genes remain poorly understood. To address this question, we analyzed the outcome of rare sarcomeric gene variants in patients enrolled in our Familial Cardiomyopathy Registry. Methods DCM families harboring rare sarcomeric variants in MYH6, MYH7, MYBPC3, TNNT2 and TTN were identified. Genotype-phenotype association analysis was performed, and long-term survival-free from death or heart transplant was compared between carriers and non-carriers. Results We found 24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2 and 13 in TTN) affecting 52 subjects in 25 families. The phenotypes of variant carriers were severe (3 sudden deaths, 6 heart failure deaths, 8 heart transplants, 2 ventricular fibrillations). There was no difference in the overall long-term survival between carriers and the 33 non-carriers (p=0.322). However after 50 years of age, the combined endpoint of death or transplant was decreased in carriers as compared to non-carriers (p=0.026). Conclusions Patients with DCM carrying rare variants in sarcomeric genes manifest a poorer prognosis as compared to non-carriers after the age of 50 years. These data further support the role genetic testing in DCM for risk stratification.

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“…We identified ten already described mutations. In the affected members of family 2 (case 5-6) and in patients 13 and 15, we identified already described changes to Proline [ 16 , 17 ]. A different missense variant (c.5401G > A/p.Glu1801Lys) segregating with the disease was identified in members of Family 3, as reported [ 7 ].…”

Section: Resultsmentioning

confidence: 96%

“…The recurrent p.Lys1617del [ 17 ] was found in three different patients (case 4, 8 and 19). A de novo synonymous mutation c.5655G > A/p.Ala1885Ala was identified in patient 18.…”

Section: Resultsmentioning

confidence: 99%

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients

Fiorillo

Astrea

Savarese

et al. 2016

Orphanet J Rare Dis

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BackgroundMyosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions.ResultsAs a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps.ConclusionThis work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0476-1) contains supplementary material, which is available to authorized users.

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Unexpectedly low mutation rates in beta‐myosin heavy chain and cardiac myosin binding protein genes in italian patients with hypertrophic cardiomyopathy

Cited by 16 publications

References 42 publications

Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein

Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein

Poor Prognosis of Rare Sarcomeric Gene Variants in Patients with Dilated Cardiomyopathy

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients

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