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Updated: Jun 3, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Developmental cardiac hypertrophy in a mouse model of prolidase deficiency
Seungwoo Jung1, Derek Silvius, Katherine A Nolan
1Department of Biomedical Sciences, Cornell University, Ithaca, New York.
Insights
A mutation in peptidase d (Pepd) causes cardiac hypertrophy in mice by affecting proline metabolism and collagen synthesis. This discovery offers a new model for studying heart defects related to prolidase deficiency.
Area of Science:
- Cardiovascular Biology
- Genetic Disease Research
- Molecular Metabolism
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary cause of sudden cardiac death in young individuals.
- Inherited HCM often stems from mutations in genes responsible for sarcomeric proteins.
- Understanding the genetic basis of HCM is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the genetic cause of embryonic cardiac hypertrophy in dark-like mutant mice.
- To explore the role of peptidase d (Pepd) and prolidase in cardiac development.
- To determine the impact of prolidase deficiency on collagen synthesis and integrin signaling in the heart.
Main Methods:
- Positional cloning to identify the dark-like mutation.
- Histologic analysis to examine cardiac morphology.
- BrdU incorporation assays to measure cardiomyocyte proliferation.
- Isolation of cardiomyocytes to assess cell size.
Main Results:
- The dark-like mutation leads to loss-of-function of peptidase d (Pepd), encoding prolidase.
- Prolidase deficiency results in cardiomyocyte hypertrophy and reduced heart chamber volume.
- Reduced levels of key integrin signaling transducers were observed in mutant embryos, suggesting a link between proline metabolism and collagen-mediated signaling.
Conclusions:
- Dark-like mice serve as a valuable model for studying prolidase deficiency and its cardiac implications.
- This research highlights the critical role of proline metabolism in maintaining normal heart physiology.
- Integrin signaling pathways may be key regulators of hypertrophic cardiac growth in response to metabolic changes.
Background:
Hypertrophic cardiomyopathy, characterized by thickened ventricular walls and reduced ventricular chamber volume, is a common cause of sudden cardiac death in young people. Most inherited forms result from mutations in genes encoding sarcomeric proteins.
Methods:
Histologic analysis identified embryonic cardiac hypertrophy in dark-like mutant mice. BrdU analysis was performed to measure proliferation and cardiomyocytes were isolated to measure cell size. The dark-like mutation was identified by positional cloning.
Results:
The dark-like mutation causes cardiomyocyte hypertrophy due to loss-of-function of peptidase d (Pepd), which encodes prolidase, a cytosolic enzyme that recycles proline for collagen re-synthesis. Prolidase deficiency is a rare autosomal recessive disease in humans with a broad phenotypic spectrum not reported to include heart defects, but a conserved role for prolidase in heart development was confirmed by morpholino knockdown in zebrafish. We tested the hypothesis that loss of prolidase function disrupts collagen-mediated integrin signaling and determined that the levels of several key integrin transducers were reduced in the hearts of dark-like mutant embryos.
Conclusions:
This work identifies dark-like mice as a model of prolidase deficiency that will be valuable for studying the role of proline metabolism in normal physiology and disease processes, and suggests that integrin signaling may regulate the onset of hypertrophic cardiac growth.
