Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations
Nature Genetics 49, 613 (2017).
doi:10.1038/ng.3815
Authors: Xia Wang, Wu-Lin Charng, Chun-An Chen, Jill A Rosenfeld, Aisha Al Shamsi, Lihadh Al-Gazali, Marianne McGuire, Nicholas Ah Mew, Georgianne L Arnold, Chunjing Qu, Yan Ding, Donna M Muzny, Richard A Gibbs, Christine M Eng, Magdalena Walkiewicz, Fan Xia, Sharon E Plon, James R Lupski, Christian P Schaaf & Yaping Yang
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.
Source: Nature Genetics - Category: Genetics & Stem Cells Authors: Xia Wang Wu-Lin Charng Chun-An Chen Jill A Rosenfeld Aisha Al Shamsi Lihadh Al-Gazali Marianne McGuire Nicholas Ah Mew Georgianne L Arnold Chunjing Qu Yan Ding Donna M Muzny Richard A Gibbs Christine M Eng Magdalena Walkiewicz Fan Xia Sharon E Plon James Tags: Letter Source Type: research