Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.
Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.
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DOI：
10.1007/s00439-016-1655-9
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发表时间：
2016-05
期刊：
影响因子：
5.3
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Szafranski P;Gambin T;Dharmadhikari AV;Akdemir KC;Jhangiani SN;Schuette J;Godiwala N;Yatsenko SA;Sebastian J;Madan-Khetarpal S;Surti U;Abellar RG;Bateman DA;Wilson AL;Markham MH;Slamon J;Santos-Simarro F;Palomares M;Nevado J;Lapunzina P;Chung BH;Wong WL;Chu YWY;Mok GTK;Kerem E;Reiter J;Ambalavanan N;Anderson SA;Kelly DR;Shieh J;Rosenthal TC;Scheible K;Steiner L;Iqbal MA;McKinnon ML;Hamilton SJ;Schlade-Bartusiak K;English D;Hendson G;Roeder ER;DeNapoli TS;Littlejohn RO;Wolff DJ;Wagner CL;Yeung A;Francis D;Fiorino EK;Edelman M;Fox J;Hayes DA;Janssens S;De Baere E;Menten B;Loccufier A;Vanwalleghem L;Moerman P;Sznajer Y;Lay AS;Kussmann JL;Chawla J;Payton DJ;Phillips GE;Brosens E;Tibboel D;de Klein A;Maystadt I;Fisher R;Sebire N;Male A;Chopra M;Pinner J;Malcolm G;Peters G;Arbuckle S;Lees M;Mead Z;Quarrell O;Sayers R;Owens M;Shaw-Smith C;Lioy J;McKay E;de Leeuw N;Feenstra I;Spruijt L;Elmslie F;Thiruchelvam T;Bacino CA;Langston C;Lupski JR;Sen P;Popek E;Stankiewicz P
肺泡毛细血管发育不良伴肺静脉错位 (ACDMPV) 是一种致命性肺部发育障碍，由 FOXF1 或其上游增强子的杂合点突变或基因组缺失拷贝数变异 (CNV) 引起，涉及胎肺表达的长非编码 RNA 基因 LINC01081 和 LINC01082。使用定制设计的阵列比较基因组杂交、桑格测序、全外显子组测序 (WES) 和生物信息学分析，我们研究了 22 个临床诊断为 ACDMPV 的新的无关家庭（20 个产后和 2 个产前）。我们描述了 13 名不相关的 ACDMPV 患者中 FOXF1 位点的新缺失 CNV。与之前报道的病例一起，16q24.1 中的所有 31 个基因组缺失（其亲本来源已确定）是从头出现的，其中 30 个缺失发生在母系遗传的 16 号染色体上，这强烈暗示了人肺中 FOXF1 基因座的基因组印记。令人惊讶的是，我们还鉴定了四个 ACDMPV 家族，其 FOXF1 位点产生于父本 16 号染色体上。有趣的是，只有在涉及 FOXF1 及其上游增强子的 CNV 缺失的儿童中，才观察到包括左心发育不全和单脐动脉在内的严重心脏缺陷的组合。我们的数据表明，16q24.1 的基因组印记可能通过 FOXF1 表达的远程调节在可变 ACDMPV 表现中发挥重要作用，并且也可能是母本单亲二体性 16 的关键表型特征的原因。此外，在一个家族中，WES 揭示了 ESRP1 中的从头错义变异，可能暗示 FGF 信号传导与 ACDMPV 的病因学有关。
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in etiology of ACDMPV.
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DOI：
10.12703/p6-75
发表时间：
2014
期刊：
F1000prime reports
影响因子：
--
作者：
Gregg C
通讯作者：
Gregg C
影响因子：
2.6
作者：
Dharmadhikari AV;Szafranski P;Kalinichenko VV;Stankiewicz P
通讯作者：
Stankiewicz P
影响因子：
4
作者：
Handrigan, Gregory Ryan;Chitayat, David;Rosenblum, Norman D.
通讯作者：
Rosenblum, Norman D.
影响因子：
3.5
作者：
Gu, Shen;Yuan, Bo;Lupski, James R.
通讯作者：
Lupski, James R.
影响因子：
4.8
作者：
Kim, IM;Zhou, Y;Kalinichenko, VV
通讯作者：
Kalinichenko, VV