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Updated: Sep 28, 2025

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis

Zhenhua Li1, Tianle Wang1, Chong Xin1

  • 1State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China.

International Journal of Biological Sciences
|March 28, 2022
PubMed

Insights

Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) deficiency causes lysosomal storage disorders and RCM-like cardiomyopathy. Restoring proteostasis attenuated cardiac dysfunction in HGS-knockout mice.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Restrictive cardiomyopathy (RCM) molecular mechanisms remain unclear.
  • Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) is key to Endosomal sorting required for transport (ESCRT) and protein homeostasis (proteostasis).
  • The role of HGS in cardiac function is unexplored.

Purpose of the Study:

  • To investigate the physiological role of HGS in cardiac homeostasis.
  • To elucidate the mechanisms by which HGS deficiency impacts cardiac function.
  • To explore HGS as a potential therapeutic target for RCM.

Main Methods:

  • Generated cardiomyocyte-specific Hgs gene knockout mice.
  • Performed proteomic analysis to identify molecular changes in knockout hearts.
  • Utilized doxycycline treatment to suppress protein aggregation.

Main Results:

  • Hgs deficiency in cardiomyocytes led to RCM-like phenotypes.
  • Loss of HGS impaired lysosomal homeostasis, disrupted cholesterol transport, and compromised lysosomal integrity.
  • Aberrant autophagosome accumulation and protein aggregation were observed, characteristic of lysosomal storage disorders (LSDs).
  • Doxycycline treatment reduced cardiac fibrosis and diastolic dysfunction in Hgs-knockout mice.

Conclusions:

  • HGS plays a critical role in maintaining cardiac lysosomal homeostasis and proteostasis.
  • HGS deficiency contributes to LSD-associated RCM-like cardiomyopathy.
  • Targeting protein aggregation may offer a therapeutic strategy for HGS-deficient cardiomyopathy.

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