Deficiency in Prader-Willi syndrome gene necdin leads to attenuated cardiac contractility

Area of Science:

• Cardiovascular Biology
• Genetics
• Molecular Medicine

Background:

• Prader-Willi syndrome (PWS) is a genetic disorder associated with cardiac abnormalities and sudden death.
• The underlying pathological mechanisms of PWS-related cardiac dysfunction are not well understood.

Purpose of the Study:

• To investigate the role of necdin, a gene in the PWS region, in cardiac function.
• To elucidate the molecular mechanisms linking necdin deficiency to heart dysfunction.

Main Methods:

• Utilized mouse models with necdin deficiency to assess cardiac function.
• Employed yeast two-hybrid screening to identify necdin-interacting proteins.
• Investigated the role of the SGT1-heat shock protein 90 (HSP90) chaperone machinery.
• Examined zebrafish models and performed cardiac-specific gene overexpression in mice.

Main Results:

• Necdin deficiency in mice resulted in impaired systolic and diastolic heart function.
• Identified an interaction between necdin and non-muscle myosin regulatory light chain 12a/b (MYL12 A/B).
• Necdin stabilizes MYL12 A/B through the SGT1-HSP90 chaperone complex.
• Zebrafish lacking the MYL12 A/B analog (MYL12.1) showed impaired heart function.
• Cardiac-specific MYL12A overexpression corrected heart dysfunction in necdin-deficient mice.

Conclusions:

• Necdin dysfunction contributes to cardiomyopathy in Prader-Willi syndrome patients.
• The SGT1-HSP90 chaperone machinery and non-muscle myosin are crucial for maintaining heart health.
• This study reveals a novel molecular pathway involved in PWS-related cardiac pathology.