Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.
Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.
复制标题
常染色体显性 Ib 型假性甲状旁腺功能减退症与杂合微缺失有关，该微缺失可能会破坏 GNAS 推定的印记控制元件。
DOI：
10.1172/jci19159
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Jüpp
中科院分区：
文献类型：
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作者：
Bastepe,Murat;Fröhlich,LeopoldF;Hendy,GeoffreyN;Indridason,OlafurS;Josse,RobertG;Koshiyama,Hiroyuki;Körkkö,Jarmo;Nakamoto,JonM;Rosenbloom,ArlanL;Slyper,ArnoldH;Sugimoto,Toshitsugu;Tsatsoulis,Agathocles;Crawford,JohnD;Jüpp
Ib型假性甲状旁腺功能减退症（PHP-Ib）患者由于肾甲状旁腺激素（PTH）抵抗而出现低钙血症和高磷血症，但缺乏Albright遗传性骨营养不良的物理特征。因此，PHP-Ib与PHP-Ia不同，后者是由编码G蛋白α亚基的GNAS外显子突变引起的。然而，PHP-Ib的印记常染色体显性形式（AD-PHP-Ib）已被定位于染色体20q13.3的含有GNAS的区域。此外，迄今为止，在所有研究的散发性PHP-Ib病例和多种AD-PHP-Ib激酶的受累成员中均观察到该基因座的差异甲基化区域（DMR）（外显子A/B）甲基化缺失。我们现在报告，12例无关的AD-PHP-Ib激酶和4例明显散发的PHP-Ib患者的受影响成员和专性基因携带者，而不是健康对照，在约220 kb的GNAS外显子A/B着丝粒处有一个约3-kb的杂合微缺失。缺失区两侧有两个正向重复序列，包括编码syntaxin-16的基因STX 16的三个外显子，没有发现印记的证据。携带微缺失的个体显示外显子A/B甲基化缺失，但在其他GNASDMR中没有表观遗传异常。因此，我们推测这种微缺失破坏了外显子A/B甲基化所需的假定的顺式作用元件，并且这种遗传缺陷是AD-PHP-Ib中肾PTH抵抗的基础。
Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in theGNASexons encoding the G protein α subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containingGNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric ofGNASexon A/B. The deleted region, which is flanked by two direct repeats, includes three exons ofSTX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at otherGNASDMRs. We therefore postulate that this microdeletion disrupts a putativecis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.