Martens J W, Verhoef-Post M, Abelin N, Ezabella M, Toledo S P, Brunner H G, Themmen A P
Department of Endocrinology and Reproduction, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.
Mol Endocrinol. 1998 Jun;12(6):775-84. doi: 10.1210/mend.12.6.0124.
Leydig cell hypoplasia (LCH) is characterized by a decreased response of the Leydig cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of cell surface expression and coupling efficiency.
莱迪希细胞发育不全（LCH）的特征是莱迪希细胞对促黄体生成素（LH）的反应降低。因此，患有这种综合征的患者表现出异常的男性发育，范围从完全性假两性畸形到阴茎短小但其他性特征正常的男性。我们评估了三名患有轻度LCH的兄弟。对他们的LH受体（LHR）基因分析发现了一个纯合错义突变，导致受体第625位的异亮氨酸残基被赖氨酸残基取代。在HEK293细胞中对这种突变型LHR，即LHR（I625K）进行的体外分析表明，信号传导效率显著受损，这解释了部分表型。我们将这种突变型LHR与分别在一名完全性和部分性LCH患者中鉴定出的另外两种突变型LHR，即LHR（A593P）和LHR（S616Y）进行了比较。尽管所有三种突变型受体的配体结合亲和力正常，但LHR（A593P）的激素反应完全缺失，而LHR（S616Y）和LHR（I625K）的激素反应严重受损。低细胞表面表达解释了LHR（S616Y）反应降低的原因，而对于LHR（I625K），这种反应减弱是由于低细胞表面表达和偶联效率降低共同导致的。对于LHR（A593P），反应未降低是由于细胞表面表达不佳和偶联完全缺陷。我们的实验进一步表明，患者临床表型的严重程度与总体受体信号能力之间存在明显相关性，总体受体信号能力是细胞表面表达和偶联效率的综合体现。
