Tsiotra Panayoula C, Koukourava Athina, Kaltezioti Valeria, Geffner Mitchell E, Naville Danielle, Begeot Martine, Raptis Sotirios A, Tsigos Constantine
Hellenic National Diabetes Center, Athens, Greece.
J Pediatr Endocrinol Metab. 2006 Sep;19(9):1157-66. doi: 10.1515/jpem.2006.19.9.1157.
Isolated glucocorticoid deficiency (IGD) is an autosomal recessive syndrome characterized by glucocorticoid insufficiency without mineralocorticoid deficiency. Mutations in the coding region of the ACTH receptor (MC2R) have been reported in several families with IGD. We amplified and sequenced the entire MC2R coding region in a new family with IGD. The proband was found to be heterozygous (paternal allele) for the mutation Gly217fs, which changes the open reading frame of the MC2R protein resulting in a truncated receptor. No other abnormality was found in the MC2R coding region. However, sequencing of the promoter region of the MC2R gene (-1017/44 bp) of the proband revealed a heterozygous T-->C substitution in the maternal allele at -2 bp position from initiation of the transcription start site. This substitution was found in only 6.5% in a healthy unrelated population. Constructs containing this polymorphism consistently showed a significant 15% decrease in promoter activity compared to wild type. In conclusion, we provide evidence that the IGD in this previously unreported family with ACTH resistance appears to be secondary to compound heterozygosity of a coding region and a promoter mutation in the MC2R gene.
孤立性糖皮质激素缺乏症（IGD）是一种常染色体隐性综合征，其特征为糖皮质激素不足但无盐皮质激素缺乏。在几个患有IGD的家族中，已报道促肾上腺皮质激素（ACTH）受体（MC2R）编码区存在突变。我们对一个新的IGD家族的整个MC2R编码区进行了扩增和测序。先证者被发现对于突变Gly217fs呈杂合子状态（父本等位基因），该突变改变了MC2R蛋白的开放阅读框，导致受体截短。在MC2R编码区未发现其他异常。然而，对先证者的MC2R基因启动子区域（-1017/44 bp）进行测序发现，在转录起始位点起始处-2 bp位置的母本等位基因中存在杂合性T→C替换。在健康无关人群中，这种替换仅占6.5%。与野生型相比，含有这种多态性的构建体始终显示启动子活性显著降低15%。总之，我们提供了证据表明，这个先前未报道的具有ACTH抵抗的家族中的IGD似乎继发于MC2R基因编码区和启动子突变的复合杂合性。
