Deficiency in Prader-Willi syndrome gene necdin leads to attenuated cardiac contractility
Yufan Dong,
Renbin Lu,
Hui Cao,
Jing Zhang,
Xiushan Wu,
Yun Deng,
Jia-Da Li
Affiliations
Yufan Dong
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P.R. China; National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410078, Hunan, P.R. China
Renbin Lu
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P.R. China; National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410078, Hunan, P.R. China
Hui Cao
State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China; Laboratory of Zebrafish Genetics, College of Life Sciences, Hunan Normal University, Changsha, China
Jing Zhang
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P.R. China; Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P.R. China; Hunan Key Laboratory of Medical Genetics, Changsha 410078, Hunan, P.R. China
Xiushan Wu
State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China; Laboratory of Zebrafish Genetics, College of Life Sciences, Hunan Normal University, Changsha, China
Yun Deng
State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China; Laboratory of Zebrafish Genetics, College of Life Sciences, Hunan Normal University, Changsha, China; Corresponding author
Jia-Da Li
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P.R. China; Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P.R. China; Hunan Key Laboratory of Medical Genetics, Changsha 410078, Hunan, P.R. China; Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases, Changsha 410078, Hunan, P.R. China; National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410078, Hunan, P.R. China; Corresponding author
Summary: 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.
