Quintero-Rivera Fabiola, Xi Qiongchao J, Keppler-Noreuil Kim M, Lee Ji Hyun, Higgins Anne W, Anchan Raymond M, Roberts Amy E, Seong Ihn Sik, Fan Xueping, Lage Kasper, Lu Lily Y, Tao Joanna, Hu Xuchen, Berezney Ronald, Gelb Bruce D, Kamp Anna, Moskowitz Ivan P, Lacro Ronald V, Lu Weining, Morton Cynthia C, Gusella James F, Maas Richard L
Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Division of Genetics, Department of Medicine.
Hum Mol Genet. 2015 Apr 15;24(8):2375-89. doi: 10.1093/hmg/ddv004. Epub 2015 Jan 7.
Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5' UTR of AHDC1, which encodes AT-hook DNA-binding motif containing-1 protein, and AHDC1-truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease [Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W. et al. (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet., 94, 784-789]. On the other hand, the 5q translocation breakpoint disrupts the 3' UTR of MATR3, which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart and great vessels, whereas Ahdc1 is not. To further establish MATR3 3' UTR disruption as the cause of the proband's LVOT defects, we prepared a mouse Matr3(Gt-ex13) gene trap allele that disrupted the 3' portion of the gene. Matr3(Gt-ex13) homozygotes are early embryo lethal, but Matr3(Gt-ex13) heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double-outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3(Gt-ex13) gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse.
心脏左心室流出道（LVOT）缺陷是先天性心脏病中常见但异质性的一个子集，其基因鉴定一直很困难。我们描述了一名46,XY,t(1;5)(p36.11;q31.2)dn易位携带者，该患者存在广泛性发育迟缓，同时还表现出LVOT缺陷，包括二叶式主动脉瓣（BAV）、主动脉缩窄（CoA）和动脉导管未闭（PDA）。1号染色体短臂断点破坏了AHDC1的5'非翻译区，AHDC1编码含AT钩DNA结合基序-1蛋白，最近在一种包括发育迟缓但不包括先天性心脏病的综合征中描述了AHDC1截短突变[Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W.等（2014年）。综合征性表达性语言迟缓、肌张力减退和睡眠呼吸暂停个体中AHDC1的新发截短突变。《美国人类遗传学杂志》，94，784 - 789]。另一方面，5号染色体长臂易位断点破坏了MATR3的3'非翻译区，MATR3编码核基质蛋白Matrin 3，而小鼠Matr3在神经嵴、发育中的心脏和大血管中强烈表达，而Ahdc1则不表达。为了进一步确定MATR3 3'非翻译区破坏是先证者LVOT缺陷的原因，我们制备了一个破坏该基因3'部分的小鼠Matr3(Gt-ex13)基因陷阱等位基因。Matr3(Gt-ex13)纯合子在胚胎早期致死，但Matr3(Gt-ex13)杂合子表现出与人类先证者相似的不完全显性的BAV、CoA和PDA表型，以及室间隔缺损（VSD）和右心室双出口（DORV）。人类MATR3易位断点和小鼠Matr3(Gt-ex13)基因陷阱插入均干扰了MATR3转录本的多聚腺苷酸化，并从定量或定性上改变了Matrin 3蛋白表达。因此，Matrin 3表达的细微扰动似乎在人类和小鼠中导致了类似的LVOT缺陷。
