Germain-Lee Emily L, Ding Chang Lin, Deng Zhichao, Crane Janet L, Saji Motoyasu, Ringel Matthew D, Levine Michael A
Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Park Building, Suite 211, 600 N. Wolfe Street, Baltimore, 21287-2520, MD, USA.
Biochem Biophys Res Commun. 2002 Aug 9;296(1):67-72. doi: 10.1016/s0006-291x(02)00833-1.
Albright hereditary osteodystrophy (AHO) is characterized by multiple somatic defects secondary to mutations in the GNAS1 gene. AHO patients with mutations on maternally inherited alleles are resistant to multiple hormones (e.g., PTH, TSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to presumed tissue-specific paternal imprinting of the alpha chain of G(s) as demonstrated in murine renal proximal tubule and fat cells. Studies in human tissues thus far revealed imprinting only in pituitary. Because mild hypothyroidism due to TSH resistance occurs in most PHP type 1a patients, we investigated whether Galpha(s) is imprinted in thyroid. Examination of eight normal thyroids demonstrated significantly greater expression from the maternal GNAS1 allele, with paternal Galpha(s) transcripts accounting for only 25.9-40.4%. Expression of NESP55, XLalpha(s), and 1A was uniallelic. We conclude that Galpha(s) is incompletely imprinted in the thyroid, which provides an explanation for mild TSH resistance in PHP type 1a.
奥尔布赖特遗传性骨营养不良（AHO）的特征是GNAS1基因突变继发的多种躯体缺陷。母系遗传等位基因发生突变的AHO患者对多种激素（如甲状旁腺激素、促甲状腺激素）耐药，这种变异称为1a型假性甲状旁腺功能减退（PHP），这是由于在小鼠肾近端小管和脂肪细胞中证实的G(s)α链存在组织特异性父系印记。迄今为止，对人体组织的研究仅发现垂体存在印记。由于大多数1a型PHP患者存在因促甲状腺激素耐药导致的轻度甲状腺功能减退，我们研究了Gα(s)在甲状腺中是否存在印记。对8个正常甲状腺组织的检测显示，母系GNAS1等位基因的表达明显更高，父系Gα(s)转录本仅占25.9 - 40.4%。NESP55、XLα(s)和1A的表达是单等位基因的。我们得出结论，Gα(s)在甲状腺中的印记不完全，这为1a型PHP中轻度促甲状腺激素耐药提供了解释。
