Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease

被引:25
作者
Alankarage, Dimuthu [1 ]
Szot, Justin O. [1 ]
Pachter, Nick [2 ,3 ]
Slavotinek, Anne [4 ,5 ]
Selleri, Licia [5 ,6 ,7 ]
Shieh, Joseph T. [4 ,5 ]
Winlaw, David [1 ,8 ,9 ]
Giannoulatou, Eleni [1 ,10 ]
Chapman, Gavin [1 ,10 ]
Dunwoodie, Sally L. [1 ,10 ]
机构
[1] Victor Chang Cardiac Res Inst, Dept Embryol, Sydney, NSW 2010, Australia
[2] King Edward Mem Hosp, Genet Serv Western Australia, Subiaco, WA 6008, Australia
[3] Univ Western Australia, Sch Paediat & Child Hlth, Nedlands, WA 6009, Australia
[4] Univ Calif San Francisco, Dept Pediat, Div Med Genet, San Francisco, CA 94158 USA
[5] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA
[6] Univ Calif San Francisco, Dept Orofacial Sci, Program Craniofacial Biol, San Francisco, CA 94143 USA
[7] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[8] Childrens Hosp Westmead, Heart Ctr Children, Sydney, NSW 2145, Australia
[9] Univ Sydney, Fac Med & Hlth, Sydney Med Sch, Discipline Child & Adolescent Hlth, Sydney, NSW 2006, Australia
[10] Univ New South Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia
基金
英国医学研究理事会; 美国国家卫生研究院;
关键词
DNA-BINDING; DE-NOVO; PBX1; MEIS2; HOX; GENETICS;
D O I
10.1093/hmg/ddz231
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pre-B cell leukemia factor 1 (PBX1) is an essential developmental transcription factor, mutations in which have recently been associated with CAKUTHED syndrome, characterized by multiple congenital defects including congenital heart disease (CHD). During analysis of a whole-exome-sequenced cohort of heterogeneous CHD patients, we identified a de novo missense variant, PBX1:c.551G>C p.R184P, in a patient with tetralogy of Fallot with absent pulmonary valve and extra-cardiac phenotypes. Functional analysis of this variant by creating a CRISPR-Cas9 gene-edited mouse model revealed multiple congenital anomalies. Congenital heart defects (persistent truncus arteriosus and ventricular septal defect), hypoplastic lungs, hypoplastic/ectopic kidneys, aplastic adrenal glands and spleen, as well as atretic trachea and palate defects were observed in the homozygous mutant embryos at multiple stages of development. We also observed developmental anomalies in a proportion of heterozygous embryos, suggestive of a dominant mode of inheritance. Analysis of gene expression and protein levels revealed that although Pbx1 transcripts are higher in homozygotes, amounts of PBX1 protein are significantly decreased. Here, we have presented the first functional model of a missense PBX1 variant and provided strong evidence that p.R184P is disease-causal. Our findings also expand the phenotypic spectrum associated with pathogenic PBX1 variants in both humans and mice.
引用
收藏
页码:1068 / 1082
页数:15
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