Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1

Area of Science:

• Cardiovascular Biology
• Genetics
• Developmental Biology

Background:

• Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by excessive trabeculation and thin compact myocardium, increasing risks of cardiac dysfunction and sudden death.
• While genetic mutations are implicated, the precise mechanisms underlying human LVNC remain poorly understood.

Purpose of the Study:

• To investigate the role of CHD4 mutations in congenital heart defects and LVNC.
• To elucidate the molecular mechanisms by which CHD4 mutations lead to ventricular wall abnormalities.

Main Methods:

• Screening of exome sequence data to identify a CHD4 mutation (CHD4M202I) in a congenital heart defect patient.
• Generation of a humanized mouse model (CHD4M195I) for mechanistic studies.
• Comprehensive analysis including histology, echocardiography, molecular assays, and chromatin immunoprecipitation.

Main Results:

• CHD4-mutant mice exhibited biventricular hypertrabeculation, noncompaction, and embryonic lethality.
• Increased cardiomyocyte proliferation and accumulation of extracellular matrix proteins due to reduced ADAMTS1 activity were observed.
• Administration of ADAMTS1 rescued hyperproliferation and hypertrabeculation defects in the mouse model.

Conclusions:

• A single mutation in the chromatin remodeler CHD4 significantly impacts ventricular chamber maturation.
• The missense mutation CHD4M195I impairs ADAMTS1 transcription, leading to impaired trabeculation termination.
• Therapeutic administration of ADAMTS1 shows potential for attenuating cardiac defects in CHD4-associated LVNC.