ENU induced mutations causing congenital cardiovascular anomalies

Development. 2004 Dec;131(24):6211-23. doi: 10.1242/dev.01543. Epub 2004 Nov 17.


We used non-invasive high frequency ultrasound to screen N-ethyl-N-nitrosourea mutagenized mouse fetuses for congenital cardiovascular anomalies. We ultrasound scanned 7546 mouse fetuses from 262 mutagenized families, and identified 124 families with cardiovascular defects. Represented were most of the major congenital cardiovascular anomalies seen clinically. The ENU-induced mutations in several families were mapped using polymorphic microsatellite DNA markers. One family with forelimb anomalies and ventricular septal defects, phenotypes similar to Holt-Oram syndrome, and one family with transposition of the great arteries and heart situs anomalies were mapped to different regions of mouse chromosome 4. A third mutation causing persistent truncus arteriosus and craniofacial defects, phenotypes reminiscent of DiGeorge syndrome, was mapped to mouse chromosome 2. We note that mouse chromosomes 4 and 2 do not contain Tbx5 or Tbx1, genes previously linked to Holt-Oram and DiGeorge syndromes, respectively. In two other families, the ENU-induced mutation was identified--Sema3CL605P was associated with persistent truncus arteriosus with interrupted aortic arch, and the Gja1W45X connexin43 mutation caused conotruncal malformation and coronary aneurysms. Although our screen was designed as a recessive screen, a number of the mutations showed cardiovascular phenotypes in both heterozygote and homozygote animals. These studies show the efficacy of ENU mutagenesis and high-throughput ultrasound phenotyping in recovering mutations causing a wide spectrum of congenital heart defects. These ENU-induced mutations hold promise in yielding new insights into the genetic basis for human congenital heart disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chromosomes, Mammalian / genetics
  • Connexin 43 / genetics
  • DiGeorge Syndrome / diagnostic imaging
  • DiGeorge Syndrome / genetics*
  • Ethylnitrosourea / toxicity*
  • Female
  • Fetus / abnormalities*
  • Heart Defects, Congenital / diagnostic imaging
  • Heart Defects, Congenital / genetics*
  • Limb Deformities, Congenital / diagnostic imaging
  • Limb Deformities, Congenital / genetics
  • Mice
  • Molecular Sequence Data
  • Mutation / drug effects*
  • T-Box Domain Proteins / genetics
  • Truncus Arteriosus, Persistent / diagnostic imaging
  • Truncus Arteriosus, Persistent / genetics
  • Ultrasonography


  • Connexin 43
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Tbx1 protein, mouse
  • Ethylnitrosourea