Identification and Functional Analysis of Novel Human Growth Hormone Secretagogue Receptor (GHSR) Gene Mutations in Japanese Subjects with Short Stature

Inoue, Hiroshi; Kangawa, Natsumi; Kinouchi, Atsuko; Sakamoto, Yukiko; Kimura, Chizuko; Horikawa, Reiko; Shigematsu, Yosuke; Itakura, Mitsuo; Ogata, Tsutomu; Fukui, Kenji

doi:10.1210/jc.2010-1570

Cited by 68 publications

(65 citation statements)

References 16 publications

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“…Later, this group also reported a patient with isolated GH deficiency due to compound heterozygous GHSR mutations (10). Similarly, a significantly higher occurrence of four novel heterozygous GHSR variants was observed in 127 Japanese patients with either GH deficiency or short stature compared with controls (4.72 vs 0.53%) (11).…”

Section: Introductionmentioning

confidence: 91%

GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood

Riedl

Hughes²,

Harris³

et al. 2012

European Journal of Endocrinology

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Context: Ghrelin plays a major role in GH physiology and energy metabolism. Polymorphisms of its receptor (GH secretagogue receptor (GHSR)) may influence childhood growth and weight regulation. Objective: To correlate GHSR polymorphisms with auxological parameters throughout childhood in a healthy cohort. Study design: Longitudinal retrospective population-based genetic association study. Subjects and methods: GHSR genotypes were evaluated in 1362 children and compared with height/length, weight, and body mass index (BMI) data across an observation span of 10 years (0, 1, 3, 5, 8, and 10 years). Five different GHSR SNPs (rs2922126, rs2981464, rs482204, rs562416, and rs572169), minor allele frequency O0.1, were genotyped. Identification of potential genetic associations with height, weight, and BMI, using additive and dominant/recessive models, was optimized by comparing allele or genotype frequencies between the tallest and the shortest 27% of subjects for each auxological variable. Significance of association was evaluated by c 2 test. Results: The rs482204 TT genotype, vs TC/CC, was associated with greater stature across the entire observation period (P!0.05). Similarly, the rs562416 TT genotype, vs TG/GG, correlated positively with tall stature at 3, 8, and 10 years. Other SNPs and genotypes showed no association with height at any age. No association was found between any tested SNPs and weight or BMI. Conclusions: Longitudinal investigation between birth and 10 years in a population-based cohort revealed a significant association of the rs482204 and rs562416 GHSR polymorphisms on height, whereas no association between GHSR polymorphisms and weight or BMI was ascertainable.

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Section: Introductionmentioning

confidence: 91%

GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood

Riedl

Hughes²,

Harris³

et al. 2012

European Journal of Endocrinology

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“…The variability of clinical phenotypes (GHD, idiopathic short stature (ISS) and constitutional delay of growth and puberty (CDGP)) and incomplete segregation of the mutations with the phenotype still cast doubt on the role of GHSR mutations in causing short stature, although functional studies do suggest that GHSR mutations may decrease GH secretion (40,41,42), implying that GHSR mutations may GHI and decreased expression or biologic activity of IGF1or IGF2 Table 2 shows the various syndromes presenting with insensitivity to GH or IGF1. The first discovered cause of GHI was Laron syndrome, usually caused by a homozygous mutation of the gene encoding the GH receptor (GHR) (43,44,45 (48,49,50) or by heterozygous GHR mutations causing a dominant negative effect (51,52,53).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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“…However, when exposed to a high-fat diet these mice are protected from diet-induced obesity [47]. A rare number of GHSR mutations have been reported in humans [48,49,50,51] and most were identified in patients with short stature. Currently, only two of the reported GHSR mutations (F279L and A204E) are connected to a higher body weight.…”

Section: Structure and Function Of Melanocortin And Ghrelin Receptorsmentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

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Identification and Functional Analysis of Novel Human Growth Hormone Secretagogue Receptor (GHSR) Gene Mutations in Japanese Subjects with Short Stature

Abstract: Our results suggest that GHSR1A mutations contribute to the genetic etiology of SS in the Japanese population.

Cited by 68 publications

References 16 publications

GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood

GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

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