Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus

Yasunari Sakai, Kazuhiro Okubo, Yuki Matsushita, Satoshi Akamine, Yoshito Ishizaki, Hiroyuki Torisu, Kenji Ihara, Masafumi Sanefuji, Min Seon Kim, Ki Up Lee, Chad A. Shaw, Janghoo Lim, Yusaku Nakabeppu, Toshiro Hara

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)475-483
Number of pages9
JournalEuropean Journal of Medical Genetics
Volume56
Issue number9
DOIs
Publication statusPublished - Sep 1 2013

Fingerprint

MEF2 Transcription Factors
Hypothalamus
Phenotype
Methyl-CpG-Binding Protein 2
Neuropeptide Y
Chromosome Disorders
Rett Syndrome
Growth Hormone-Releasing Hormone
Arcuate Nucleus of Hypothalamus
Interneurons
Appetite
Hypothermia
Hypoglycemia
Intellectual Disability
Small Interfering RNA
Growth Hormone
Genes
Arginine
Seizures
Insulin

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus. / Sakai, Yasunari; Okubo, Kazuhiro; Matsushita, Yuki; Akamine, Satoshi; Ishizaki, Yoshito; Torisu, Hiroyuki; Ihara, Kenji; Sanefuji, Masafumi; Kim, Min Seon; Lee, Ki Up; Shaw, Chad A.; Lim, Janghoo; Nakabeppu, Yusaku; Hara, Toshiro.

In: European Journal of Medical Genetics, Vol. 56, No. 9, 01.09.2013, p. 475-483.

Research output: Contribution to journalArticle

Sakai, Yasunari ; Okubo, Kazuhiro ; Matsushita, Yuki ; Akamine, Satoshi ; Ishizaki, Yoshito ; Torisu, Hiroyuki ; Ihara, Kenji ; Sanefuji, Masafumi ; Kim, Min Seon ; Lee, Ki Up ; Shaw, Chad A. ; Lim, Janghoo ; Nakabeppu, Yusaku ; Hara, Toshiro. / Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus. In: European Journal of Medical Genetics. 2013 ; Vol. 56, No. 9. pp. 475-483.
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AU - Okubo, Kazuhiro

AU - Matsushita, Yuki

AU - Akamine, Satoshi

AU - Ishizaki, Yoshito

AU - Torisu, Hiroyuki

AU - Ihara, Kenji

AU - Sanefuji, Masafumi

AU - Kim, Min Seon

AU - Lee, Ki Up

AU - Shaw, Chad A.

AU - Lim, Janghoo

AU - Nakabeppu, Yusaku

AU - Hara, Toshiro

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N2 - 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.

AB - 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.

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