Search

CN-122012515-A - Hypertrophic cardiomyopathy pathogenic gene MYH7c.794C > T (p.Thr265Ile) and application thereof

CN122012515ACN 122012515 ACN122012515 ACN 122012515ACN-122012515-A

Abstract

The invention belongs to the technical fields of biological medicine and molecular biology, and provides a hypertrophic cardiomyopathy pathogenic gene MYH7 c.794C > T (p.Thr265Ile) and application thereof. The MYH7 gene mutation is located in the 9 th exon, the 794 th base is mutated from C to T, namely, ACC is mutated to ATC, and the 265 th amino acid in the coded amino acid sequence is mutated from threonine to isoleucine. The mutation induces cardiac hypertrophy by disrupting energy metabolism-this defect occurs before contractile dysfunction occurs. With the increasing prominence of accurate medicine in cardiovascular treatment, a treatment strategy aiming at upstream pathological processes (such as energy steady state imbalance and mitochondrial dysfunction) provides a promising approach for preventing and treating MYH 7-related hypertrophic cardiomyopathy. MYH7 gene screening is of great value in facilitating early diagnosis, guiding timely therapeutic intervention, and achieving risk-based preventive management.

Inventors

  • LIU HUIRONG
  • HAO YANYAN
  • WU YE
  • ZHANG SULI

Assignees

  • 首都医科大学

Dates

Publication Date
20260512
Application Date
20260202

Claims (6)

  1. 1. The hypertrophic cardiomyopathy pathogenic gene MYH7 c.794C > T (p.Thr265Ile) is characterized in that MYH7 gene mutation is located in 9 th exon, 794 th base is mutated from C to T, namely ACC is mutated to ATC, and 265 th amino acid in an encoded amino acid sequence is mutated from threonine to isoleucine.
  2. 2. The hypertrophic cardiomyopathy causative gene MYH7 c.794C > T (p.Thr265Ile) according to claim 1, wherein the MYH7 c.794C > T (p.Thr265Ile) mutation is located in the head domain of the beta-MHC, near the ATP binding site, and the ATP binding affinity of the mutein is reduced.
  3. 3. The method according to claim 1, wherein the mutation of MYH7 c.794C > T (p.Thr265Ile) drives key pathological features of hypertrophic cardiomyopathy including cardiomyocyte hypertrophy, mitochondrial injury, energy metabolism disorder and calcium regulation disorder.
  4. 4. The hypertrophic cardiomyopathy causative gene MYH7 c.794C > T (p.Thr265Ile) according to claim 1, wherein the mutation of MYH7 c.794C > T (p.Thr265Ile) causes a change in cardiac structure in a sex-dependent manner.
  5. 5. The method according to claim 1, wherein the mutation of MYH7 c.794C > T (p.Thr265Ile) results in the pathological exacerbation of hypertrophic cardiomyopathy with age.
  6. 6. The use of the hypertrophic cardiomyopathy pathogenic gene MYH7 c.794c > T (p.thr265ile) of claim 1 in the preparation of a kit for detection or early diagnosis of hypertrophic cardiomyopathy.

Description

Hypertrophic cardiomyopathy pathogenic gene MYH7c.794C > T (p.Thr265Ile) and application thereof Technical Field The invention belongs to the technical fields of biological medicine and molecular biology, and particularly relates to a hypertrophic cardiomyopathy pathogenic gene MYH7c.794C > T (p.Thr265Ile) and application thereof. Background Hypertrophic Cardiomyopathy (HCM) is the most common primary cardiomyopathy, with global prevalence estimated at 1:500 to 1:200. The disease is a major cause of sudden death in teenagers and athletes. The combination of the American Heart Association/American society of cardiology/American society of motion medicine/society of cardiac rhythms/European society of cardiology/society of cardiac pathology, published by the United states of America heart Association/American society of cardiology, emphasized that hypertrophic cardiomyopathy constitutes a significant public health burden, indicating that accurate gene diagnosis and personalized sudden death risk stratification are the central links of clinical management. The myosin heavy chain gene 7 (MYH 7) encoding the β -myosin heavy chain (β -MHC) is the major causative gene of hypertrophic cardiomyopathy, accounting for about 30% to 50% of familial cases. A number of pathogenic mutations are concentrated in the globular head domain of the protein and in the transition region of the head to rod-like structure. The perturbation of the microstructure of these functionally critical regions can trigger diverse molecular pathophysiological consequences. However, about 25-30% of clinically definite cardiomyopathy patients lack identifiable pathogenic mutations, revealing a significant gap in MYH7 mutation profile cognition today-particularly rare mutations involving critical functional regions, the mechanism role of which remains insufficiently elucidated. Traditionally, MYH 7-related pathological mechanisms are attributed to excessive sarcomere contraction, where mutations in the globular head and adjacent transition regions enhance calcium sensitivity, leading to increased tone generation and increased contractile activity. However, emerging evidence shifts focus to metabolic disorders. Existing studies show that mutations affecting the myosin head may impair ATP utilization efficiency, thereby causing a primary energy loss. It was subsequently demonstrated that myocardial energy metabolism dysfunction, mitochondrial damage and related oxidative stress may be early causative drivers of hypertrophic cardiomyopathy. These pathological changes occur independently of, and possibly prior to, overt contractile dysfunction, establishing a pathogenic axis centered on the interaction of energy metabolism, calcium processing and mitochondrial integrity. Disclosure of Invention The invention provides a hypertrophic cardiomyopathy pathogenic gene MYH7c.794C > T (p.Thr265Ile) and application thereof. The invention is realized by the following technical scheme that the pathogenic gene MYH7c.794C > T (p.Thr265Ile) of hypertrophic cardiomyopathy, wherein the mutation of the MYH7 gene is located in the 9 th exon, the base at 794 th is mutated from C to T, namely ACC to ATC, and the amino acid at 265 th is mutated from threonine to isoleucine in the coded amino acid sequence. The myh7c.794c > T (p.thr265ile) mutation is located in the head domain of β -MHC, close to the ATP binding site, with reduced ATP binding affinity of the mutein. The myh7c.794c > T (p.thr265ile) mutation drives key pathological features of hypertrophic cardiomyopathy, including cardiomyocyte hypertrophy, mitochondrial injury, energy metabolism disorder and calcium regulation disorder. The myh7c.794c > T (p.thr265ile) mutation leads to cardiac structural changes and mitochondrial dysfunction in a gender dependent manner. The myh7c.794c > T (p.thr265ile) mutation results in a pathological exacerbation of hypertrophic cardiomyopathy with age. The invention also provides application of the hypertrophic cardiomyopathy pathogenic gene MYH7c.794C > T (p.Thr265Ile) in preparation of a kit for detecting or early diagnosing the hypertrophic cardiomyopathy. The invention identifies a novel missense mutation in a large Chinese autosomal dominant inherited hypertrophic cardiomyopathy family, MYH7c.794C > T (p.Thr265 Ile). The mutation is located at the interface between the myosin head domain and the head-rod transition region, which is highly conserved among different species, and is closely related to the efficiency of mechanochemical coupling during ATP hydrolysis and lever arm movement. However, the mutation is not found in genome databases at home and abroad, and the pathogenicity, molecular mechanism and potential association with energy metabolism driving pathogenic pathways are not elucidated. Notably, clinical observations showed that the forerunner developed symptoms at puberty, while their father only developed a hypertrophic cardiomyopathy phenotype after adulthood, sugg