Familial Pseudohypoparathyroidism Type IB Associated with an SVA Retrotransposon Insertion in the GNAS Locus
Familial Pseudohypoparathyroidism Type IB Associated with an SVA Retrotransposon Insertion in the GNAS Locus
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IB 型家族性假性甲状旁腺功能减退症与 GNAS 基因座中 SVA 逆转录转座子插入相关
DOI：
10.1002/jbmr.4652
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Masayo Kagami
中科院分区：
文献类型：
--
作者：
Sayaka Kawashima;Akiko Yuno;Shinichiro Sano;Masayo Kagami
GNAS-A/B的甲基化缺失(LOM)：在假性甲状旁腺功能减退症1B型(PHP1B)中观察到GNAS基因座上的差异甲基化区域(DMRS)。许多PHP1B病例是散发性的，但常染色体显性遗传性PHP1B缺失涉及母体等位基因表达的NESP55或位于母体等位基因GNAS基因座上游的STX16。我们报告了第一例可能的家族性PHP1B病例，其母系等位基因上的GNAS基因座上有反转录转座子插入。据我们所知，它们可能是第一例由反转录转座子插入引起的印迹障碍。这两个兄弟姐妹从学龄期起就出现手足抽筋和/或痉挛，并有低钙血症和血清完整甲状旁腺激素(PTH)水平升高，同时伴有超重、圆脸和正常智力水平。对GNAS基因座DMR的甲基化分析仅显示了GNAS-A/B：TSS-DMR的LOM。阵列比较基因组杂交未检测到STX16和GNAS基因座的拷贝数异常。全基因组测序和Sanger测序显示，在这些兄弟姐妹中，在GNAS基因座A/B的第一个外显子上游插入了大约1000个碱基的SVA反转录转座子。对这些同胞进行的全基因组甲基序列分析显示，插入位点周围区域处于正常甲基化状态，GNAS-A/B：TSS-DMR有轻微的LOM。我们用皮肤成纤维细胞的mRNA进行了转录组分析，并诱导了来自兄弟姐妹的多能干细胞(IPSCs)，没有检测到NESP55的异常转录。皮肤成纤维细胞定量逆转录聚合酶链式反应(qRT-PCR)分析显示，患者A/B表达增加，NESP55表达阴性，甚至在对照组也不表达。定量逆转录-聚合酶链式反应分析显示，患者NESP55表达降低，GNAS-NESP：TSS-DMR甲基化状态正常。在同胞中插入反转录转座子可能导致NESP55表达降低，这可能通过GNAS-A/B：Tss-DmR的LOM导致A/B表达增加，随后Gsα表达降低，最终导致PHP1B的发展。©2022美国骨与矿物研究学会(ASBMR)。
Loss of methylation (LOM) at GNAS‐A/B:TSS‐differentially methylated regions (DMRs) in the GNAS locus is observed in pseudohypoparathyroidism type 1B (PHP1B). Many PHP1B cases are sporadic, but autosomal dominant‐PHP1B has a deletion involving NESP55 expressed from the maternal allele or STX16 located upstream of the GNAS locus on the maternal allele. We report the possible first familial PHP1B cases with retrotransposon insertion in the GNAS locus on the maternal allele. To our knowledge, they are the possible first cases with imprinting disorders caused by retrotransposon insertion. The two sibling cases experienced tetany and/or cramps from school age and had hypocalcemia and an increased serum intact parathyroid hormone (PTH) level together with overweight, round face, and normal intellectual levels. Methylation analysis for DMRs in the GNAS locus showed only LOM of the GNAS‐A/B:TSS‐DMR. Copy number abnormalities at STX16 and the GNAS locus were not detected by array comparative genomic hybridization. Whole‐genome sequencing and Sanger sequencing revealed an approximately 1000‐bp SVA retrotransposon insertion upstream of the first exon of A/B on the GNAS locus in these siblings. Whole‐genome methylome analysis by Enzymatic Methyl‐Seq in the siblings showed normal methylation status in the region surrounding the insertion site and mild LOM of the GNAS‐A/B:TSS‐DMR. We conducted transcriptome analysis using mRNA from skin fibroblasts and induced pluripotent stem cells (iPSCs) derived from the siblings and detected no aberrant NESP55 transcripts. Quantitative reverse‐transcriptase PCR (qRT‐PCR) analysis in skin fibroblasts showed increased A/B expression in the patients and no NESP55 expression, even in a control. qRT‐PCR analysis in iPSCs showed decreased NESP55 expression with normal methylation status of the GNAS‐NESP:TSS‐DMR in the patients. The retrotransposon insertion in the siblings likely caused decreased NESP55 expression that could lead to increased A/B expression via LOM of the GNAS‐A/B:TSS‐DMR, subsequent reduced Gsα expression, and finally, PHP1B development. © 2022 American Society for Bone and Mineral Research (ASBMR).
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影响因子：
5.7
作者：
Rochtus A;Martin-Trujillo A;Izzi B;Elli F;Garin I;Linglart A;Mantovani G;Perez de Nanclares G;Thiele S;Decallonne B;Van Geet C;Monk D;Freson K
通讯作者：
Freson K
影响因子：
3.7
作者：
Monk, David;Morales, Joannella;Tumer, Zeynep
通讯作者：
Tumer, Zeynep
影响因子：
3.7
作者：
Fuke T;Mizuno S;Nagai T;Hasegawa T;Horikawa R;Miyoshi Y;Muroya K;Kondoh T;Numakura C;Sato S;Nakabayashi K;Tayama C;Hata K;Sano S;Matsubara K;Kagami M;Yamazawa K;Ogata T
通讯作者：
Ogata T
DOI：
--
发表时间：
2015
期刊：
--
影响因子：
--
作者：
S. Turan;M. Bastepe
通讯作者：
S. Turan;M. Bastepe