title: Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Chun-An
authors.initials: CA
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Pediatrics, Tawam Hospital, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Aisha
authors.initials: A
authors.lastname: Al Shamsi
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Baylor Genetics, Houston, Texas, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: McGuire
authors.affiliation: Rare Diseases Institute, Children's National Health System, Washington, DC, USA.
authors.forename: Nicholas Ah
authors.initials: NA
authors.lastname: Mew
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: Georgianne L
authors.initials: GL
authors.lastname: Arnold
authors.affiliation: Baylor Genetics, Houston, Texas, USA.
authors.forename: Chunjing
authors.initials: C
authors.lastname: Qu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Christian P
authors.identifier: http://orcid.org/0000-0002-2148-7490
authors.initials: CP
authors.lastname: Schaaf
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002460:Cell Line; D025063:Chromosome Disorders / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D001068:Feeding and Eating Disorders / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010677:Philadelphia Chromosome / Q000187:drug effects; D010766:Phosphorylation / Q000235:genetics; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016044:Fusion Proteins, bcr-abl