ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension
ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension
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DOI：
10.1111/j.1399-0004.2011.01727.x
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发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Soubrier, F.
中科院分区：
文献类型：
--
作者：
Eyries, M.;Coulet, F.;Soubrier, F.
Eyries M，Coulet F，Girerd B，Montani D，Humbert M，Lacombe P，Chinet T，Gouya L，Roume J，Axford MM，Pearson CE，Soubrier F.ACVRL1生发马赛克和两个突变的等位基因在遗传性出血性毛细血管扩张合并肺动脉高压中的作用。转化生长因子-β(TGF-β)/骨形态发生蛋白(BMP)超家族成员基因的胚系突变是导致遗传性出血性毛细血管扩张症(HHT)和遗传性肺动脉高压(PAH)的两种遗传性血管疾病的原因。当两种疾病并存时，通常会发现激活素A受体II样激酶-1(ACVRL1)基因突变。我们报告了一个显著的ACVRL1生发和体细胞嵌合症，其特征是存在两个不同的突变等位基因和一个非突变的ACVRL1等位基因，该患者在40岁时被诊断为PAH。根据毛细血管扩张、鼻出血和动静脉畸形的其他发现，她也符合库拉索关于HHT的诊断标准。ACVRL1的突变分析发现，在外显子10中有两个相邻的杂合性有害突变：c.1388del(p.Gly463fsX2)和c.1390del(p.Leu464X)，位于突变相关DNA基序丰富的区域。母亲将c.1388del传给了一个孩子，并将c.1390del传给了两个孩子，证实了生殖细胞嵌合体。等位基因特异性聚合酶链式反应分析显示，在该指征病例的淋巴细胞中，c.1388del是主要突变。单倍型分析表明，两个突变的等位基因具有共同的染色体起源，这与母亲的非突变的ACVRL1等位基因不同。这些组织和生殖系中不同的突变等位基因可能是在母亲胚胎发育的早期阶段发生的DNA结构介导的事件产生的，在她的生殖系分离之前，这最终导致了每个等位基因的独立传递。这些突显了早期胚胎发育过程中发生的基因组事件的复杂性以及突变嵌合体对致病变异性的影响。
Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Germline mutations in genes encoding members of the transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curacao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.