title: Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus.
abstract: The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus.
authors.affiliation: Department of Pediatrics, Kyushu University Hospital, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: ysakai22q13@gmail.com.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohkubo
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akamine
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ishizaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Torisu
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sanefuji
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Janghoo
authors.initials: J
authors.lastname: Lim
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D000818:Animals; D025063:Chromosome Disorders / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007003:Hypoglycemia / Q000175:diagnosis / Q000235:genetics; D007031:Hypothalamus / Q000254:growth & development / Q000378:metabolism*; D007035:Hypothermia / Q000175:diagnosis / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013577:Syndrome
chemical_list: D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C497393:Mecp2 protein, mouse; C578041:Mef2c protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009478:Neuropeptide Y
keywords: 5q14.3 Deletion syndrome; Hypothalamus; Myocyte-specific enhancer factor 2C (MEF2C); Neuropeptide Y (NPY)