功能丧失型GHSR变体与身材矮小和低胰岛素样生长因子I相关。

Loss-of-Function GHSR Variants Are Associated With Short Stature and Low IGF-I.

作者信息

Punt Lauren D, Kooijman Sander, Mutsters Noa J M, Yue Kaiming, van der Kaay Daniëlle C M, van Tellingen Vera, Bakker-van Waarde Willie M, Boot Annemiek M, van den Akker Erica L T, van Boekholt Anneke A, de Groote Kirsten, Kruijsen Anne R, van Nieuwaal-van Maren Nancy H G, Woltering M Claire, Heijligers Malou, van der Heyden Josine C, Bannink Ellen M N, Rinne Tuula, Hannema Sabine E, de Waal Wouter J, Delemarre Lucia C, Rensen Patrick C N, de Bruin Christiaan, van Duyvenvoorde Hermine A, Visser Jenny A, Delhanty Patric J D, Losekoot Monique, Wit Jan M, Joustra Sjoerd D

机构信息

Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands.

Division of Endocrinology, Department of Medicine, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands.

出版信息

J Clin Endocrinol Metab. 2025 Apr 22;110(5):e1303-e1314. doi: 10.1210/clinem/dgaf010.

DOI:10.1210/clinem/dgaf010

PMID:39785833

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12012706/

Abstract

CONTEXT

The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knockout mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting, but patient observations in small case reports have been equivocal.

OBJECTIVE

This work aims to establish the phenotype of GHSR haploinsufficiency and its growth response to GH treatment.

METHODS

This case series includes 26 patients with short stature and heterozygous GHSR variants. Pathogenicity was studied in vitro using total protein levels, cell surface expression, and receptor activity in basal, stimulated, and inhibited states.

RESULTS

Ten different variants were identified, of which 6 were novel. Variants showed either partial or complete loss of function, primarily through loss of constitutive activity. Patients (aged 4.0-15.1 years) had proportionate short stature (height -2.8 ± 0.5 SDS), failure to thrive with low appetite (n = 4), a mean serum insulin-like growth factor-I (IGF-I) of -1.6 ± 0.7 SDS, and a normal stimulated GH response. Nine patients received GH treatment, showing a height gain of 0.9 ± 0.4 SDS after 1 year and 1.5 ± 0.4 SDS after 2 years (n = 5).

CONCLUSION

This study combines phenotypical and functional data in a uniquely large group of children with short stature carrying GHSR variants, and shows their good response to GH treatment. The results strengthen the hypothesis of GHSR's role in GH secretion.

摘要

背景

生长激素（GH）促分泌素受体由GHSR编码，表达于垂体生长激素细胞上。用其配体胃饥饿素刺激以及其组成性活性均可增强GH分泌。基因敲除小鼠研究表明，GHSR杂合功能丧失与禁食后GH反应降低有关，但小病例报告中的患者观察结果并不明确。

目的

本研究旨在确定GHSR单倍体不足的表型及其对GH治疗的生长反应。

方法

本病例系列包括26例身材矮小且携带GHSR杂合变异的患者。使用总蛋白水平、细胞表面表达以及基础、刺激和抑制状态下的受体活性在体外研究致病性。

结果

鉴定出10种不同的变异，其中6种为新变异。变异主要通过组成性活性丧失表现出部分或完全功能丧失。患者年龄在4.0至15.1岁之间，身材匀称矮小（身高标准差评分-2.8±0.5），食欲低下导致生长发育不良（n = 4），血清胰岛素样生长因子-I（IGF-I）平均标准差评分为-1.6±0.7，刺激后的GH反应正常。9例患者接受了GH治疗，1年后身高标准差评分增加0.9±0.4，2年后增加1.5±0.4（n = 5）。