Goddard A D, Dowd P, Chernausek S, Geffner M, Gertner J, Hintz R, Hopwood N, Kaplan S, Plotnick L, Rogol A, Rosenfield R, Saenger P, Mauras N, Hershkopf R, Angulo M, Attie K
Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94060, USA.
J Pediatr. 1997 Jul;131(1 Pt 2):S51-5. doi: 10.1016/s0022-3476(97)70012-x.
Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.
生长激素受体（GHR）基因座的突变可能通过损害生长激素（GH）受体功能在特发性矮小症（ISS）的病因中起作用。在一个极端情况下，使GH受体功能丧失的突变与完全性GH不敏感综合征或拉龙综合征相关，我们推测破坏性较小的突变可能导致部分性GH不敏感综合征。低水平的GH结合蛋白可能表明受体细胞外结构域存在突变，通过聚焦于14名患有ISS且GH结合蛋白和胰岛素样生长因子I水平较低的儿童，我们发现了3名杂合子和1名受体细胞外结构域突变的复合杂合子。此后，我们将研究扩展到更广泛的患者群体，在一项关于重组人生长激素治疗ISS的安全性和有效性的II期研究中增加了76名接受GH治疗的ISS患者，还增加了10名在私人诊所被儿科内分泌学家确诊为ISS的患者。因此，我们对100名ISS患者的GHR基因进行了分析，其中8人被发现携带突变：4人在我们最初的研究中，4人GH结合蛋白水平正常或升高。后一组包括3名细胞外结构域杂合突变携带者和1名细胞内结构域杂合突变携带者。家族数据表明，这些突变携带者具有一系列表型，支持了我们的假设，即这些杂合突变表现为部分性GH不敏感综合征取决于个体的基因构成。
