Salvatori R, Fan X, Phillips J A, Espigares-Martin R, Martin De Lara I, Freeman K L, Plotnick L, Al-Ashwal A, Levine M A
Division of Endocrinology, Department of Medicine, Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
J Clin Endocrinol Metab. 2001 Jan;86(1):273-9. doi: 10.1210/jcem.86.1.7156.
Isolated GH deficiency (IGHD) is familial in 5-30% of cases. The majority of patients have the type IB form, characterized by autosomal recessive transmission, low but measurable serum concentrations of GH, and responsiveness to exogenous GH therapy. Unique mutations in the gene encoding the GHRH receptor (GHRHR) have previously been described in 2 kindreds with IGHD IB. However, the prevalence of GHRHR mutations in patients with IGHD IB is unknown. We analyzed 30 families with IGHD IB in which more than 1 member was affected. Linkage analysis was performed in 28 of the families, and in 3 families sibling pair analysis indicated linkage to the GHRHR gene locus. These 3 families as well as 2 families in which linkage analysis was not performed were screened for mutations in the 13 coding exons, the intron-exon boundaries, and 327 bases of the promoter of the GHRHR gene. We identified novel GHRHR missense mutations in 2 of the 3 kindreds with informative linkage and in 1 family in which linkage had not been performed. In 1 family affected members were homozygous for a mutation in codon 144 that replaces leucine with histidine (L144H). Affected subjects in a second family were compound heterozygotes, carrying both the L144H mutation and a second mutation in codon 242 that replaces phenylalanine with cysteine. Affected subjects in a third family were homozygous for a mutation that replaces alanine at codon 222 with glutamic acid. All 3 mutations segregated with the IGHD phenotype. All 3 mutant receptors were expressed in CHO cells, and each failed to show a cAMP response after treatment of the cells with GHRH. These results demonstrate that missense mutations in the GHRHR gene are a cause of IGHD IB, and that defects in the GHRHR gene may be a more common cause of GH deficiency than previously suspected.
孤立性生长激素缺乏症（IGHD）在5% - 30%的病例中具有家族性。大多数患者为IB型，其特征为常染色体隐性遗传、血清生长激素浓度低但可检测到，且对外源性生长激素治疗有反应。先前在2个患有IGHD IB的家族中描述了编码生长激素释放激素受体（GHRHR）的基因中的独特突变。然而，IGHD IB患者中GHRHR突变的发生率尚不清楚。我们分析了30个有不止1名成员受影响的IGHD IB家族。对其中28个家族进行了连锁分析，在3个家族中，同胞对分析表明与GHRHR基因座连锁。对这3个家族以及未进行连锁分析的2个家族进行了筛查，检测GHRHR基因的13个编码外显子、内含子 - 外显子边界以及启动子的327个碱基中的突变。我们在3个具有信息性连锁的家族中的2个以及1个未进行连锁分析的家族中鉴定出了新的GHRHR错义突变。在1个家族中，受影响成员在密码子144处发生突变，导致亮氨酸被组氨酸取代（L144H），为纯合子。在第二个家族中，受影响的受试者为复合杂合子，携带L144H突变以及密码子242处的第二个突变，该突变导致苯丙氨酸被半胱氨酸取代。在第三个家族中，受影响的受试者为纯合子，其密码子222处的丙氨酸被谷氨酸取代。所有这3种突变均与IGHD表型共分离。所有3种突变受体均在CHO细胞中表达，在用生长激素释放激素处理细胞后，每种受体均未显示出cAMP反应。这些结果表明，GHRHR基因中的错义突变是IGHD IB的一个病因，并且GHRHR基因缺陷可能是生长激素缺乏比先前怀疑的更常见的原因。
