Sano Shinichiro, Nakamura Akie, Matsubara Keiko, Nagasaki Keisuke, Fukami Maki, Kagami Masayo, Ogata Tsutomu
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
J Endocr Soc. 2017 Nov 21;2(1):9-23. doi: 10.1210/js.2017-00293. eCollection 2018 Jan 1.
Pseudohypoparathyroidism type I (PHP-I) is divided into PHP-Ia with Albright hereditary osteodystrophy and PHP-Ib, which usually shows no Albright hereditary osteodystrophy features. Although PHP-Ia and PHP-Ib are typically caused by genetic defects involving subunit of the stimulatory G protein (Gs)-coding exons and methylation defects of the differentially methylated regions (DMRs) on the maternal allele, respectively, detailed phenotypic characteristics still remains to be examined.
To clarify phenotypic characteristics according to underlying (epi)genetic causes.
We performed (epi)genotype-phenotype analysis in 69 Japanese patients with PHP-I; that is, 28 patients with genetic defects involving Gs-coding exons (group 1) consisting of 12 patients with missense variants (subgroup A) and 16 patients with null variants (subgroup B), as well as 41 patients with methylation defects (group 2) consisting of 21 patients with broad methylation defects of the -DMRs (subgroup C) and 20 patients with an isolated -DMR methylation defect accompanied by the common microdeletion (subgroup D).
Although (epi)genotype-phenotype findings were grossly similar to those reported previously, several important findings were identified, including younger age at hypocalcemic symptoms and higher frequencies of hyperphosphatemia in subgroup C than in subgroup D, development of brachydactyly in four patients of subgroup C, predominant manifestation of subcutaneous ossification in subgroup B, higher frequency of thyrotropin resistance in group 1 than in group 2, and relatively low thyrotropin values in four patients with low T4 values and relatively low luteinizing hormone/follicle-stimulating hormone values in five adult females with ovarian dysfunction.
The results imply the presence of clinical findings characteristic of each underlying cause and provide useful information on the imprinting status of Gs.
I型假性甲状旁腺功能减退症（PHP-I）分为伴有奥尔布赖特遗传性骨营养不良的PHP-Ia型和通常无奥尔布赖特遗传性骨营养不良特征的PHP-Ib型。虽然PHP-Ia型和PHP-Ib型通常分别由涉及刺激性G蛋白（Gs）编码外显子的亚基的基因缺陷和母源等位基因上差异甲基化区域（DMR）的甲基化缺陷引起，但详细的表型特征仍有待研究。
根据潜在的（表观）遗传病因阐明表型特征。
我们对69例日本PHP-I患者进行了（表观）基因型-表型分析；即28例涉及Gs编码外显子基因缺陷的患者（第1组），其中12例为错义变异患者（A亚组）和16例无义变异患者（B亚组），以及41例甲基化缺陷患者（第2组），其中21例为-DMR广泛甲基化缺陷患者（C亚组）和20例伴有常见微缺失的孤立-DMR甲基化缺陷患者（D亚组）。
虽然（表观）基因型-表型结果与先前报道的结果大致相似，但发现了一些重要结果，包括C亚组低钙血症症状出现年龄较D亚组小，高磷血症发生率更高；C亚组4例患者出现短指畸形；B亚组皮下骨化为主；第1组促甲状腺激素抵抗发生率高于第2组；4例T4值低的患者促甲状腺激素值相对较低，5例卵巢功能障碍成年女性黄体生成素/促卵泡激素值相对较低。
结果提示每种潜在病因都有其特征性临床表现，并为Gs的印记状态提供了有用信息。
