生长激素受体基因突变与非生长激素缺乏性矮身材的相关研究

目的了解生长激素受体（GHR）基因突变与非生长激素缺乏性矮小的相关性,以及GHR基因突变患儿的临床特点。方法（1）选择47例（男33例,女14例,年龄2—16岁）非生长激素缺乏而又显著矮小的患儿作为研究对象;80例身高正常的儿童（男49例,女31例,年龄1—17岁）作为对照组。（2）应用PCR-SSCP和基因测序技术检测GHR突变。（3）通过家系成员和正常对照人群的基因分析以及氨基酸同源序列分析等,推测突变基因的性质。结果（1）在47例矮小患儿中有5例、4种不同的GHR基因突变：H56R、G148E、IVS6-30,-31CA〉TG和IVS8＋10G〉C。5例患儿均为杂合突变,杂合突变个体的检出频率为10．6％（5／47）。（2）对照组的基因分析显示这些突变非多态性改变,初步认为H56R和G148E突变可能对蛋白功能产生影响。（3）确定了1种多态性突变：G168G（GGA〉GGG）。该位点基因频率的分布在矮小儿童组和正常对照组之间的差异无统计学意义,但与西方白种人之间的差异有统计学意义。提示该突变可能是单核苷酸多态性改变,与身高没有相关关系。但该位点的等位基因存在人种的差异。结论非生长激素缺乏性矮身材患儿存在GHR基因杂合突变。

Mutation of growth hormone receptor gene in patients with short stature

Objectives The mutations of growth hormone receptor(GHR)gene results in growth hormone insensitivity(Laron syndrome)or partial growth hormone insensitivity.This study aimed to understand the relation between mutations of GHR gene and short stature with non-growth-hormone deficiency,and the clinical feature of the patients with the GHR gene mutations.Methods(1)Forty-seven patients with non-growth-hormone deficiency and short stature were enrolled in this study,33 were male and 14 female.The age of the patients were at a range of 2-16 years.(2)The mutations of GHR gene were identified by PCR-SSCP and DNA sequencing.(3)The characteristics of the GHR mutation was assumed by screening for the same mutations in patients' family members and the control samples.Results(1)Four GHR mutations were identified in 5 patients with non-growth-hormone deficiency:H56R,G148E,IVS6-30,-31CA>TG and IVS8+10G>C.These mutations were located within the extracellular domain of GHR and not reported before.Five patients were the heterozygous of H56R,G148E,IVS6-30,-31CA>TG and IVS8+10G>C.The detection rate of mutant heterozygous individual accounted for 10.6%(5/47).The mutations were considered non-polymorphism by the GHR gene analysis in patients' family members and control samples.(2)Comparison of the amino acid sequence of different species and the position of the mutations H56R and G148E in the GHR protein structure suggested impact of the mutations on the protein function.(3)A polymorphism site was identified in exon 6 of GHR gene:G168G(GGA>GGG).The allelic frequency of G168G had no difference between the patients with non-growth-hormone deficiency and control samples but had significant difference between Chinese and Caucasian.It seems that the G168G was a polymorphism and has no relationship with the height stature.However,there was the allele diversity in different races.Conclusion The mutations of GHR gene were detected in the patients with non-growth-hormone deficiency.Special attention should be paid clinically to its potential pathogenesis for short stature.