摘要
目的探讨儿童生长激素不敏感综合征（GHIS）的分子病因及临床表型的相关性。方法对21例临床诊断GHIS患儿的4个关联候选基因（GHR、IGFALS、JAK2和STAT5B）进行基因组DNA序列筛查与临床关联参数分析。结果所有患儿平均身高标准差（standarddeviation，SDS）-4．33±1．91（-9．17—-2．21），平均血清GH峰值（22．67±20．98）μg／L（11．33—104．21μg／L），基础血清胰岛素样生长因子ISDS-2．65±0．53（-3．57～-1．79）、胰岛素样生长因子结合蛋白3SDS—1．77±1．64（-4．13～0．96）；骨龄较实际年龄落后差值（实际年龄-骨龄）为（43．10±19．54）个月（6～82个月）。在2例伴面中部发育不良的重型矮小者中发现1例GHR第六内含子5’剪接位点纯合突变（IVS6ds＋1G—A）。3例轻型矮小者被发现IGFALS基因新发变异：c．1097T〉Cc．1098C〉TP．V366A（复合杂合型）、c．1229C〉Tp．S410L（杂合型）、5’UTR区染色体第1843707位碱基A→G（纯合型）。JAK2、STAT5b基因未发现突变。结论GHIS是原发性胰岛素样生长因子I缺乏的重要病因，其分子病理涉及GHR及受体后信号通路缺陷。本文21例GHIS患儿中仅发现1例GHR突变和3例IGFALS变异。提示GHR和IGFALS缺陷可能参与致病，但并不是其主要分子缺陷，更多的分子病理机制尚有待进一步深入研究。
Objective To detect the relationship between the molecular defects and their phenotypes in children with growth hormone insensitivity syndrome （ GHIS）. Methods 21 patients defined as GHIS were enrolled in the study. 4 candidate genes （GHR, IGFALS, JAK2, and STATSB） were analyzed by genomic DNA sequence screening and clinical relevance analysis. Results The statistical descriptions of the patients were showed as an average height standard deviation （SDS） -4.33 ± 1.91 （ -9.17 to -2.21 ）, average serum peak values of GH （22.67 -± 20.98） μg/L （ 11.33 to 104.21 μg/L）, basal serum insulin-like growth factor- I SDS -2.65 ±- 0. 53 （ -3.57 to - 1.79） , insulin-like growth factor-binding protein 3 SDS - 1.77 ± 1.64 （ -4. 13 to 0.96 ）. Bone age of backward difference （ chronological age-bone age） （43.10 ±19.54 ） months （6 to 82 months）. One of two children with severe growth failure and mid-face hypoplasia was found to a homozygote for G to A gene mutation in the intron 6 splice donor consensus sequences （ IVS6 ds± 1 G-A） in the GHR gene, causing its functional defect. 3 cases with mild dwarf were found gene variations as novel finding： c. 1097T〉C c. 1098C〉T p. V366A pathogenic variant, c. 1229C〉T p. S410L and nt1843707 A→G of 5＇UTR region in the IGFALS gene. JAK2 and STATS b genes mutations were not found. Conclusion Molecular pathology of GHIS is considered as involving the defects of GHR and its signal pathway. The mutation of intron 6 splice donor sequences in GHR gene has been reported which affect the function of GHR. The 3 novel type base variants in IGFALS gene, causing non severe dwarfism, might be suspected with pathogenic roles of GHIS.
出处
《中华内分泌代谢杂志》
CAS
CSCD
北大核心
2015年第12期1046-1050,共5页
Chinese Journal of Endocrinology and Metabolism
