High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects
High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects
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DOI：
10.1210/clinem/dgab460
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发表时间：
2021-06-22
影响因子：
5.8
通讯作者：
Levine, Michael A.
中科院分区：
文献类型：
--
作者：
Danzig, Jennifer;Li, Dong;Levine, Michael A.
内容：1b型假性甲状旁腺功能减退症（PHP 1b）患者表现出母亲GNAS等位基因或父亲单亲二体性（UPD）的印记紊乱。STX 16或GNAS上游外显子的遗传缺失存在于许多家族性但非散发性病例中。目的：表征PHP 1b患者的表观遗传和遗传缺陷。设计和患者：DNA来自84名受试者，包括26名散发性PHP 1b受试者，27名受影响受试者和17名来自12个PHP 1b家族的未受影响和/或专性基因携带者，11名健康个体，结果：健康受试者、未受影响的家庭成员和父亲PHP 1b等位基因的专性携带者以及PHP 1a受试者均显示所有DMR的正常甲基化。所有PHP 1 B受试者均显示外显子A/B DMR的甲基化缺失（LOM）。9个PHP 1 B激酶家族成员仅在外显子A/B DMR处出现LOM，其中7个家族存在STX 16外显子4 ~ 6的3-kb缺失，1个家族存在STX 16和邻近NEPEPL 1的新缺失。一个新的NESP缺失被发现在2个更广泛的甲基化缺陷的其他家庭。一个散发性PHP 1b有UPD的20 q，2个有3-kb STX 16缺失，5个有明显的表观遗传mosaicis.Conclusions：我们发现了不同的模式的缺陷甲基化和确定新的或以前已知的突变在9个12 PHP 1b家庭。
Context: Patients with pseudohypoparathyroidism type 1b (PHP1b) show disordered imprinting of the maternal GNAS allele or paternal uniparental disomy (UPD). Genetic deletions in STX16 or in upstream exons of GNAS are present in many familial but not sporadic cases.Objective: Characterization of epigenetic and genetic defects in patients with PHP1b.Design and Patients: DNA from 84 subjects, including 26 subjects with sporadic PHP1b, 27 affected subjects and 17 unaffected and/or obligate gene carriers from 12 PHP1b families, 11 healthy individuals, and 3 subjects with PHP1a was subjected to quantitative pyrosequencing of GNAS differentially methylated regions (DMRs), microarray analysis, and microsatellite haplotype analysis.Setting: Academic medical center.Main Outcome Measurements: Molecular pathology of PHP1b.Results: Healthy subjects, unaffected family members and obligate carriers of paternal PHP1b alleles, and subjects with PHP1a showed normal methylation of all DMRs. All PHP1b subjects showed loss of methylation (LOM) at the exon A/B DMR. Affected members of 9 PHP1b kindreds showed LOM only at the exon A/B DMR, which was associated with a 3-kb deletion of STX16 exons 4 through 6 in 7 families and a novel deletion of STX16 and adjacent NEPEPL1 in 1 family. A novel NESP deletion was found in 1 of 2 other families with more extensive methylation defects. One sporadic PHP1b had UPD of 20q, 2 had 3-kb STX16 deletions, and 5 had apparent epigenetic mosaicism.Conclusions: We found diverse patterns of defective methylation and identified novel or previously known mutations in 9 of 12 PHP1b families.