Wu S M, Stratakis C A, Chan C H, Hallermeier K M, Bourdony C J, Rennert O M, Chan W Y
Department of Pediatrics, Georgetown University, Washington, DC 20007, USA.
Mol Genet Metab. 1998 Aug;64(4):256-65. doi: 10.1006/mgme.1998.2724.
Hereditary primary adrenal insufficiency syndromes due to ACTH resistance include hereditary glucocorticoid deficiency (HGD) and Allgrove's syndrome (AS). Patients with both conditions present in childhood with failure to thrive, weakness, and fatigue or adrenal crisis; patients with AS in addition have alacrima and achalasia (triple A syndrome). We studied four kindreds with HGD and four kindreds with AS for abnormalities of the ACTH receptor (ACTHR) gene. The ACTHR coding sequence in all AS kindreds and two HGD kindreds was normal. Analysis of the ACTHR gene of the proband in one of the HGD kindreds showed him to be homozygous for the previously described G221T transition causing a Ser74Ile substitution of the protein, which has been shown to inactivate the ACTHR in signal transduction. The proband in another HGD kindred was found to be a compound heterozygote with the G221T transition in one allele and a novel C818A transition in the other allele of ACTHR. The C818A transition caused the substitution of the highly conserved Pro273 by His in the receptor protein. In vitro expression of the mutated ACTHR in mouse melanoma M3 cells showed that at a medium ACTH concentration of 3 nM, cells transfected with the wild-type ACTHR produced twofold and threefold, respectively, of the amount of intracellular cAMP when compared to cells transfected with the ACTHR carrying the Pro273His and the Ser74Ile mutation, respectively, confirming that HGD in this kindred is caused by loss-of-function mutations of the ACTHR. These results showed that the genetic cause of the ACTH-resistant syndromes is heterogeneous.
由于促肾上腺皮质激素（ACTH）抵抗导致的遗传性原发性肾上腺皮质功能不全综合征包括遗传性糖皮质激素缺乏症（HGD）和阿尔格罗夫综合征（AS）。这两种疾病的患者在儿童期均表现为生长发育迟缓、虚弱、疲劳或肾上腺危象；AS患者还伴有泪腺分泌减少和贲门失弛缓症（三联征）。我们研究了四个患有HGD的家族和四个患有AS的家族，以寻找促肾上腺皮质激素受体（ACTHR）基因的异常情况。所有AS家族和两个HGD家族的ACTHR编码序列均正常。对其中一个HGD家族先证者的ACTHR基因分析显示，他对于先前描述的导致蛋白质中Ser74Ile替代的G221T转换是纯合的，该转换已被证明在信号转导中使ACTHR失活。另一个HGD家族的先证者被发现是复合杂合子，其ACTHR的一个等位基因中有G221T转换，另一个等位基因中有新的C818A转换。C818A转换导致受体蛋白中高度保守的Pro273被His替代。在小鼠黑色素瘤M3细胞中对突变的ACTHR进行体外表达研究表明，在促肾上腺皮质激素浓度为3 nM的培养基中，与分别转染携带Pro273His和Ser74Ile突变的ACTHR的细胞相比，转染野生型ACTHR的细胞产生的细胞内cAMP量分别高出两倍和三倍，这证实该家族中的HGD是由ACTHR功能丧失突变引起的。这些结果表明，ACTH抵抗综合征的遗传病因是异质性的。
