Identification of a novel splicing mutation in the growth hormone (GH)-releasing hormone receptor gene in a Chinese family with pituitary dwarfism

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:313

Article

Wang, Qi¹  Diao, Ying²  Xu, Zhenping^1,3  Luo, Xiao Ping⁴  Xu, Haibo⁵  Ouyang, Ping¹  Liu, Mugen¹  Hu, Zhongli²  Wang, Qing K.^1,6  Liu, Jing Yu¹ 

[1] Huazhong Univ Sci & Technol, Key Lab Mol Biophys, Minist Educ, Ctr Human Genome Res, Wuhan 430074, Peoples R China

[2] Wuhan Univ, Coll Life Sci, Minist Educ Plant Dev Biol, Key Lab, Wuhan 430072, Peoples R China

[3] Xinxiang Med Coll, Dept Life Sci & Tech, Xinxiang 453003, Peoples R China

[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Pediat, Wuhan 430030, Peoples R China

[5] Huazhong Univ Sci & Technol, Union Hosp, Dept Radiol, Wuhan 430022, Peoples R China

[6] Cleveland Clin Fdn, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44195 USA

关键词: Inherited pituitary dwarfism;    GHRHR;    Linkage and sequence analysis;    Splice mutation;    In vitro transcription analysis;   

DOI  :  10.1016/j.mce.2009.08.021

来源: Elsevier

【 摘 要 】

A Chinese family with autosomal recessive pituitary dwarfism was identified and the proband was evaluated by MRI and hormonal analysis, which revealed pituitary dwarfism with a complete growth hormone deficiency. MRI showed a pituitary gland with a small anterior pituitary of 2.2 mm and evidence of hypoplastic pituitary. Linkage analysis with markers spanning 17 known genes for dwarfism revealed linkage of the family to the growth hormone-releasing hormone receptor (GHRHR) gene. Mutational analysis of all exons and exon-intron boundaries of GHRHR was carried out using direct DNA sequence analysis. A novel homozygosis mutation, a G to A transition located in the splice donor site at the beginning of intron 8 (IVS8+1G>A), was identified in the proband. The two other patients in the family are homozygous, whereas the living mother of the proband is heterozygous for the IVS8+1G>A mutation. The mutation was not found in 100 normal chromosomes from healthy Chinese individuals of Han nationality. An in vitro splicing assay using HeLa cells transfected with expression vectors containing the normal or the mutant GHRHR minigenes consisting of genomic fragments spanning exons 7-9 showed that the IVS8+1G>A mutation caused abnormal splicing, which is predicted to give rise to truncation or frameshift, leading to severely truncated GHRHR proteins. These results provide strong evidence that the splicing mutation IVS8+1G>A of GHRHR is a cause of pituitary dwarfism in the Chinese family. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

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