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Nat Genet. 2017 Apr;49(4):613-617. doi: 10.1038/ng.3815. Epub 2017 Mar 13.

Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
2
Baylor Genetics, Houston, Texas, USA.
3
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
4
Department of Pediatrics, Tawam Hospital, Al-Ain, Abu Dhabi, United Arab Emirates.
5
Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates.
6
Rare Diseases Institute, Children's National Health System, Washington, DC, USA.
7
Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
8
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
9
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
10
Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA.

Abstract

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

PMID:
28288113
PMCID:
PMC5373987
DOI:
10.1038/ng.3815
[Indexed for MEDLINE]
Free PMC Article

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