2. Academic Validation
  3. Deficiency in Prader-Willi syndrome gene necdin leads to attenuated cardiac contractility

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

  • iScience. 2024 May 14;27(6):109974. doi: 10.1016/j.isci.2024.109974.
Yufan Dong 1 2,  Renbin Lu 1 2,  Hui Cao 3 4,  Jing Zhang 1 5 6,  Xiushan Wu 3 4,  Yun Deng 3 4,  Jia-Da Li 1 5 6 7 2
Affiliations

Affiliations

  • 1 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P.R. China.
  • 2 National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410078, Hunan, P.R. China.
  • 3 State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.
  • 4 Laboratory of Zebrafish Genetics, College of Life Sciences, Hunan Normal University, Changsha, China.
  • 5 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P.R. China.
  • 6 Hunan Key Laboratory of Medical Genetics, Changsha 410078, Hunan, P.R. China.
  • 7 Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases, Changsha 410078, Hunan, P.R. China.
PMID: 38832028 DOI: 10.1016/j.isci.2024.109974
Abstract

Prader-Willi syndrome (PWS) is a genetic disorder characterized by behavioral disturbances, hyperphagia, and intellectual disability. Several surveys indicate that PWS is also associated with cardiac abnormalities, possibly contributing to a high incidence of sudden death. However, the pathological mechanisms underlying cardiac dysfunction in PWS remain unclear. In this study, we found that deficiency in necdin, an intronless gene within PWS region, led to heart systolic and diastolic dysfunction in mice. Through yeast two-hybrid screening, we identified an interaction between necdin and non-muscle Myosin regulatory light chain 12a/b (MYL12 A/B). We further showed that necdin stabilized MYL12 A/B via SGT1-heat shock protein 90 (HSP90) chaperone machinery. The zebrafish lacking the MYL12 A/B analog, MYL12.1, exhibited impaired heart function, while cardiac-specific overexpression of MYL12A normalized the heart dysfunction in necdin-deficient mice. Our findings revealed necdin dysfunction as a contributing factor to cardiomyopathy in PWS patients and emphasized the importance of HSP90 chaperone machinery and non-muscle Myosin in heart fitness.

Keywords

cardiovascular medicine; genetics; molecular biology.

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