Departments of Paediatrics and Paediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Autonomous University of Barcelona, CIBERER (Centre for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain.
Clin Endocrinol (Oxf). 2012 Oct;77(4):564-74. doi: 10.1111/j.1365-2265.2012.04410.x.
Molecular causes of isolated severe growth hormone deficiency (ISGHD) in several genes have been established. The aim of this study was to analyse the contribution of growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to GH deficiency in a series of prepubertal ISGHD patients and to normal adult height.
DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GHRHR gene sequence analysis was performed in 69 ISGHD patients and 60 normal adult height controls (NAHC). Four GHRHR single-nucleotide polymorphisms (SNPs) were genotyped in 248 additional NAHC. An analysis was performed on individual SNPs and combined genotype associations with diagnosis in ISGHD patients and with height-SDS in NAHC.
Twenty-one SNPs were found. P3, P13, P15 and P20 had not been previously described. Patients and controls shared 12 SNPs (P1, P2, P4-P11, P16 and P21). Significantly different frequencies of the heterozygous genotype and alternate allele were detected in P9 (exon 4, rs4988498) and P12 (intron 6, rs35609199); P9 heterozygous genotype frequencies were similar in patients and the shortest control group (heights between -2 and -1 SDS) and significantly different in controls (heights between -1 and +2 SDS). GHRHR P9 together with 4 GH1 SNP genotypes contributed to 6·2% of height-SDS variation in the entire 308 NAHC.
This study established the GHRHR gene sequence variation map in ISGHD patients and NAHC. No evidence of GHRHR mutation contribution to ISGHD was found in this population, although P9 and P12 SNP frequencies were significantly different between ISGHD and NAHC. Thus, the gene sequence may contribute to normal adult height, as demonstrated in NAHC.
孤立性生长激素缺乏症（ISGHD）的几个基因的分子病因已经确定。本研究旨在分析生长激素释放激素受体（GHRHR）基因序列变异对一系列青春期前 ISGHD 患者和正常成人身高的 GH 缺乏的影响。
设计、受试者和测量方法：对 69 例 ISGHD 患者和 60 例正常成人身高对照组（NAHC）进行了系统的 GHRHR 基因序列分析。在另外 248 名 NAHC 中，对 4 个 GHRHR 单核苷酸多态性（SNP）进行了基因分型。对个体 SNP 以及与 ISGHD 患者诊断和 NAHC 身高-SDS 的组合基因型关联进行了分析。
发现了 21 个 SNP。P3、P13、P15 和 P20 以前没有被描述过。患者和对照组共享 12 个 SNP（P1、P2、P4-P11、P16 和 P21）。在 P9（外显子 4，rs4988498）和 P12（内含子 6，rs35609199）中，杂合基因型和交替等位基因的频率有显著差异。在患者和最短对照组（身高在-2 和-1 SDS 之间）中，P9 杂合基因型频率相似，而在对照组（身高在-1 和+2 SDS 之间）中则有显著差异。GHRHR P9 与 4 个 GH1 SNP 基因型共同导致了整个 308 名 NAHC 中 6.2%的身高-SDS 变异。
本研究建立了 ISGHD 患者和 NAHC 的 GHRHR 基因序列变异图谱。在该人群中，没有发现 GHRHR 突变导致 ISGHD 的证据，尽管 P9 和 P12 SNP 频率在 ISGHD 和 NAHC 之间有显著差异。因此，正如在 NAHC 中所证明的那样，该基因序列可能对正常成人身高有贡献。
