Rare genetic mutations in Pakistani patients with dilated cardiomyopathy

Shakeel, Muhammad; Irfan, Muhammad; Khan, Ishtiaq Ahmad

doi:10.1016/j.gene.2018.06.019

Cited by 23 publications

(16 citation statements)

References 45 publications

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“…It could be that the loss of one or both of these protein interactions allows myomesin to translocate to the cytoplasm or nucleus [63,64]. Support for this displacement of myomesin comes from the lack of detectable myomesin incorporated into diseased/damaged sarcomeres (Figs 5 & 7) and the high concentration of myomesin 3 protein in the sera of Duchenne muscular dystrophy, Limb-girdle muscular dystrophy and dilated cardiomyopathy patients and animal models [45,60–62,65]. We showed that the absence of myosin or the C-terminus of titin can prevent myomesin from incorporating into the sarcomere and that it is not paralysis or contractions in a defective sarcomere that displace myomesin in these fish (Fig 6).…”

Section: Discussionmentioning

confidence: 99%

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

et al. 2019

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The structure and function of the sarcomere of striated muscle is well studied but the steps of sarcomere assembly and maintenance remain under-characterized. With the aid of chaperones and factors of the protein quality control system, muscle proteins can be folded and assembled into the contractile apparatus of the sarcomere. When sarcomere assembly is incomplete or the sarcomere becomes damaged, suites of chaperones and maintenance factors respond to repair the sarcomere. Here we show evidence of the importance of the M-line proteins, specifically myomesin, in the monitoring of sarcomere assembly and integrity in previously characterized zebrafish muscle mutants. We show that myomesin is one of the last proteins to be incorporated into the assembling sarcomere, and that in skeletal muscle, its incorporation requires connections with both titin and myosin. In diseased zebrafish sarcomeres, myomesin1a shows an early increase of gene expression, hours before chaperones respond to damaged muscle. We found that myomesin expression is also more specific to sarcomere damage than muscle creatine kinase, and our results and others support the use of myomesin assays as an early, specific, method of detecting muscle damage.

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Section: Discussionmentioning

confidence: 99%

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

et al. 2019

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“…While the role of TauT deletion in the advent of the 3p-syndrome (OMIM#613792, Patel et al, 1995 ; Han, Budreau, Chesney, & Sturman, 2000 ) is unclear, disease relevant loss-of-function mutations in TauT mimic the phenotypic features of TauT −/− mice. Homozygous deletion of the splice site between exon 8 and 9 of TauT was associated with dilated cardiomyopathy in one patient ( Shakeel, Irfan, & Khan, 2018 ). Biallelic mutations in TauT that encode the p.(A78E) and p.(G399V) variants ( Table 4 ) were identified in siblings from 2 unrelated families suffering from rapidly progressive childhood retinal degeneration ( Ansar et al, 2020 ; Preising et al, 2019 ), accompanied by cardiomyopathy ( Ansar et al, 2020 ).…”

Section: Slc6 Family: Monogenic Diseases Associated With Tra...mentioning

confidence: 99%

Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits

Bhat

El‐Kasaby

Freissmuth

et al. 2021

Pharmacology & Therapeutics

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“…By adopting a GWAS strategy, performed in the largest population of DCM assembled so far, we identified and replicated two new susceptibility loci for DCM while confirming two previously reported DCM associated ones, HSPB7 and BAG3. (42). Taurine (TAU) is a highly concentrated amino-acide with cyto-protective action in numerous tissues, especially in contractile ones such as heart (43).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, XPC (p = 8.3 10 -15 ) and SLC6A6 (p = 6.9 10 -6 ) LV expressions were significantly increased in DCM patients compared to healthy donors ( Supplementary Table 7A) while LSM3 expression was significantly decreased (p = 7.6 10 -8 ). Functional candidate at this locus may include TMEM43, implied in arrhythmogenic right ventricular cardiomyopathy (ARVC) (39)(40)(41), and SLC6A6, for which a homozygous deletion affecting a splice site was found by whole-exome sequencing in a patient with idiopathic DCM (42).…”

Section: Heritabilitymentioning

confidence: 99%

Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosome 3p25.1 and 22q11.23

Garnier

Harakaľová

Weiß

et al. 2020

Preprint

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SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.

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Rare genetic mutations in Pakistani patients with dilated cardiomyopathy

Cited by 23 publications

References 45 publications

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits

Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosome 3p25.1 and 22q11.23

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