Linglart Agnès, Maupetit-Méhouas Stéphanie, Silve Caroline
Endocrinology and Diabetology for Children and French Center of Reference for Rare Disorders of Calcium and Phosphorus Metabolism, Bicêtre-Paris-Sud Hospital, Le Kremlin Bicêtre, France.
Horm Res Paediatr. 2013;79(3):119-29. doi: 10.1159/000348516. Epub 2013 Mar 29.
GNAS (guanine nucleotide-binding protein, α stimulating) is a complex imprinted locus coding, besides the α-stimulatory subunit of the G protein, the paternally (extra-large, antisense and A/B) and maternally (neuroendocrine secretory protein) transcripts. Heterozygous mutations in the coding sequence of GNAS produce dominant phenotypes (combination of resistances to hormones signaling through G-protein-coupled receptors, osteodystrophy and obesity) that depend on the parental origin of the mutated allele. Likewise, alterations in the methylation at promoters of GNAS transcripts, associated or not with deletions of imprinting control regions in the nearby STX16 gene or within GNAS, prompt resistance to parathormone when affecting the maternal allele. Therefore, imprinting of GNAS is the determining factor for the variability of the phenotype. Knowledge of the various phenotypes is necessary for genetic counseling as well as an appropriate therapeutic balance between regular follow-up, prevention of disease complications and iatrogeny.
GNAS（鸟嘌呤核苷酸结合蛋白，α刺激型）是一个复杂的印记基因座，除了编码G蛋白的α刺激亚基外，还编码父本转录本（超大、反义及A/B）和母本转录本（神经内分泌分泌蛋白）。GNAS编码序列中的杂合突变会产生显性表型（对通过G蛋白偶联受体的激素信号传导的抗性、骨营养不良和肥胖的组合），这些表型取决于突变等位基因的亲本来源。同样，GNAS转录本启动子处的甲基化改变，无论是否与附近STX16基因或GNAS内印记控制区域的缺失相关，当影响母本等位基因时都会导致对甲状旁腺激素的抗性。因此，GNAS的印记是表型变异性的决定因素。了解各种表型对于遗传咨询以及在定期随访、预防疾病并发症和医源性疾病之间实现适当的治疗平衡至关重要。
