Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency

Akiko Soneda, Masanori Adachi, Koji Muroya, Yumi Asakura, Masaki Takagi, Tomonobu Hasegawa, Hiroshi Inoue, Mitsuo Itakura

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Objective: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. Design: A 2-year-old girl of height 77.2. cm (-. 3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7. ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41. μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81. ng/mL with insulin-induced hypoglycemia, 3.78. ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (. GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. Results: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2. +. 3a. >. g mutation would lead to aberrant splicing. Conclusions: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.

Original languageEnglish
Pages (from-to)89-97
Number of pages9
JournalGrowth Hormone and IGF Research
Volume23
Issue number4
DOIs
Publication statusPublished - 2013 Aug

Fingerprint

Pituitary Dwarfism
Luciferases
Mutation
Hormones
Genes
Consanguinity
Growth Hormone-Releasing Hormone
Insulin-Like Growth Factor Binding Protein 3
Somatomedins
Hypoglycemia
varespladib methyl
Growth Hormone
Fluorescent Antibody Technique
Arginine
Pharmacology
Insulin
somatotropin releasing hormone receptor

Keywords

  • Growth hormone-releasing hormone receptor
  • Isolated growth hormone deficiency
  • Pituitary hypoplasia
  • Short stature
  • Splice donor site

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency. / Soneda, Akiko; Adachi, Masanori; Muroya, Koji; Asakura, Yumi; Takagi, Masaki; Hasegawa, Tomonobu; Inoue, Hiroshi; Itakura, Mitsuo.

In: Growth Hormone and IGF Research, Vol. 23, No. 4, 08.2013, p. 89-97.

Research output: Contribution to journalArticle

Soneda, Akiko ; Adachi, Masanori ; Muroya, Koji ; Asakura, Yumi ; Takagi, Masaki ; Hasegawa, Tomonobu ; Inoue, Hiroshi ; Itakura, Mitsuo. / Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency. In: Growth Hormone and IGF Research. 2013 ; Vol. 23, No. 4. pp. 89-97.
@article{a99543019dbb4deba6afad1f0f8748f3,
title = "Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency",
abstract = "Objective: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. Design: A 2-year-old girl of height 77.2. cm (-. 3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7. ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41. μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81. ng/mL with insulin-induced hypoglycemia, 3.78. ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (. GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. Results: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2. +. 3a. >. g mutation would lead to aberrant splicing. Conclusions: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.",
keywords = "Growth hormone-releasing hormone receptor, Isolated growth hormone deficiency, Pituitary hypoplasia, Short stature, Splice donor site",
author = "Akiko Soneda and Masanori Adachi and Koji Muroya and Yumi Asakura and Masaki Takagi and Tomonobu Hasegawa and Hiroshi Inoue and Mitsuo Itakura",
year = "2013",
month = "8",
doi = "10.1016/j.ghir.2013.03.003",
language = "English",
volume = "23",
pages = "89--97",
journal = "Endocrinology and Metabolism",
issn = "1096-6374",
publisher = "Churchill Livingstone",
number = "4",

}

TY - JOUR

T1 - Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency

AU - Soneda, Akiko

AU - Adachi, Masanori

AU - Muroya, Koji

AU - Asakura, Yumi

AU - Takagi, Masaki

AU - Hasegawa, Tomonobu

AU - Inoue, Hiroshi

AU - Itakura, Mitsuo

PY - 2013/8

Y1 - 2013/8

N2 - Objective: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. Design: A 2-year-old girl of height 77.2. cm (-. 3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7. ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41. μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81. ng/mL with insulin-induced hypoglycemia, 3.78. ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (. GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. Results: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2. +. 3a. >. g mutation would lead to aberrant splicing. Conclusions: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.

AB - Objective: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. Design: A 2-year-old girl of height 77.2. cm (-. 3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7. ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41. μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81. ng/mL with insulin-induced hypoglycemia, 3.78. ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (. GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. Results: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2. +. 3a. >. g mutation would lead to aberrant splicing. Conclusions: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.

KW - Growth hormone-releasing hormone receptor

KW - Isolated growth hormone deficiency

KW - Pituitary hypoplasia

KW - Short stature

KW - Splice donor site

UR - http://www.scopus.com/inward/record.url?scp=84878655434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878655434&partnerID=8YFLogxK

U2 - 10.1016/j.ghir.2013.03.003

DO - 10.1016/j.ghir.2013.03.003

M3 - Article

C2 - 23602557

AN - SCOPUS:84878655434

VL - 23

SP - 89

EP - 97

JO - Endocrinology and Metabolism

JF - Endocrinology and Metabolism

SN - 1096-6374

IS - 4

ER -