Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.
Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.
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DOI：
10.1111/j.1365-2265.2006.02709.x
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发表时间：
2007-02
影响因子：
3.2
通讯作者：
Achermann JC
中科院分区：
文献类型：
--
作者：
Lin L;Hindmarsh PC;Metherell LA;Alzyoud M;Al-Ali M;Brain CE;Clark AJ;Dattani MT;Achermann JC
家族性糖皮质激素缺乏症 I 型 (FGD1) 是一种罕见的原发性肾上腺皮质功能不全，由 ACTH 受体（MC2R、MC2R）隐性突变引起。患有这种疾病的个体通常在婴儿期或儿童期出现皮质醇不足的体征和症状，但肾素-血管紧张素系统、醛固酮合成或钠稳态的紊乱并不是 FGD1 与 FGD1 之间的关联。由于 ACTH 刺激已被证明可以刺激正常对照中醛固酮的释放，并且皮质醇缺乏症儿童中也可能发生低钠血症的其他原因，因此我们研究了在接受盐皮质激素不足治疗的原发性肾上腺衰竭儿童中是否可能发现 MC2R 变化。通过直接测序对 MC2R 进行突变分析。被诊断患有失盐型肾上腺发育不全的儿童 (n = 22)（19 例孤立病例，3 例家族性病例），且 DAX1 (NR0B1) 和 SF1 (NR5A1) 突变呈阴性。在三个个体或亲属中发现了 MC2R 突变（I：纯合 S74I；II：新型复合杂合 R146H/560delT；III：新型纯合 579-581delTGT）。这些变化代表了这种 G 蛋白偶联受体的严重破坏性功能丧失突变，包括首次报道的纯合移码突变。钠稳态的明显紊乱是轻微的，在应激时表现出来（例如感染、限盐、热），并且可能随着时间的推移而消失。对于原发性肾上腺功能衰竭且肾素钠稳态明显轻度紊乱的儿童，应考虑 MC2R 突变。这些儿童可能被误诊为失盐性肾上腺发育不全。做出这一诊断对于治疗、咨询和长期预后具有重要意义。
Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. Mutational analysis of MC2R by direct sequencing. Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.
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影响因子：
3.5
作者：
Slavotinek, AM;Hurst, JA;Wilkie, AOM
通讯作者：
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