Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Bone. 2011 Mar 1;48(3):659-62. doi: 10.1016/j.bone.2010.10.168. Epub 2010 Oct 19.
Pseudohypoparathyoridism type Ib (PHP-Ib) typically defines the presence of end-organ resistance to parathyroid hormone in the absence of Albright's hereditary osteodystrophy. Patients affected by this disorder present with imprinting defects in the complex GNAS locus. Microdeletions within STX16 or GNAS have been identified in familial cases with PHP-Ib, but the molecular cause of the GNAS imprinting defects in sporadic PHP-Ib cases remains poorly defined. We now report a case with sporadic PHP-Ib for whom a SNPlex analysis revealed loss of the maternal GNAS allele. Further analysis of the entire genome with a 100K SNP chip identified a paternal uniparental isodisomy affecting the entire chromosome 20 without evidence for another chromosomal abnormality. Our findings explain the observed GNAS methylation changes and the patient's hormone resistance, and furthermore suggest that chromosome 20 harbors, besides GNAS, no additional imprinted region that contributes to the clinical and laboratory phenotype.
假性甲状旁腺功能减退症 1b 型（PHP-Ib）通常定义为在没有阿耳布赖特遗传性骨营养不良的情况下存在甲状旁腺激素的靶器官抵抗。受这种疾病影响的患者在 GNAS 基因座存在印迹缺陷。在具有 PHP-Ib 的家族性病例中已经鉴定出 STX16 或 GNAS 内的微缺失，但散发性 PHP-Ib 病例中 GNAS 印迹缺陷的分子原因仍未明确定义。我们现在报告了一例散发性 PHP-Ib 病例，SNPlex 分析显示母源性 GNAS 等位基因缺失。用 100K SNP 芯片对整个基因组进行进一步分析，发现一条父源性单亲二体性影响整个 20 号染色体，但没有其他染色体异常的证据。我们的发现解释了观察到的 GNAS 甲基化变化和患者的激素抵抗，并且进一步表明 20 号染色体除了 GNAS 之外，没有其他印迹区域有助于临床和实验室表型。
