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Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS

机译:Ib型常染色体显性伪低甲状旁腺功能亢进症与杂合性微缺失有关,该杂合性微缺失可能破坏GNAS的假定印迹控制元件。

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摘要

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 the GNAS exons 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 containing GNAS. 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 of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, 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 other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.
机译:Ib型假性甲状旁腺功能减退症(PHP-Ib)患者由于肾副甲状旁腺激素(PTH)抵抗而发生低钙血症和高磷酸盐血症,但缺乏Albright遗传性骨营养不良的身体特征。因此,PHP-1b与PHP-1a不同,PHP-1b是由编码G蛋白α亚基的GNAS外显子突变引起的。但是,已将印迹的常染色体显性形式的PHP-Ib(AD-PHP-Ib)映射到含有GNAS的20q13.3染色体区域。此外,到目前为止,在所有调查的零星PHP-Ib病例和多个AD-PHP-Ib亲属的受影响成员中,都观察到了该基因座的差异甲基化区域(DMR)外显子A / B处的甲基化损失。我们现在报告,受影响的成员和12个不相关的AD-PHP-Ib亲属和4个明显零星的PHP-Ib患者(但不是健康对照)的专职基因携带者具有杂合性,大约3kb的微缺失,位于GNAS外显子A的大约220kb / B。缺失的区域两侧是两个直接重复序列,包括三个STX16外显子,STX16是编码syntaxin-16的基因,找不到该基因的印记。进行微缺失的受影响个体在其他GNAS DMR上显示外显子A / B甲基化缺失,但没有表观遗传异常。因此,我们推测该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肾PTH耐药性的基础。

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