Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity
Open Access
- 22 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 29 (4), 593-603
- https://doi.org/10.1038/s41431-020-00766-w
Abstract
ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib.Keywords
Funding Information
- DH | National Institute for Health Research (RP-2016-07-011, RP-2016-07-011)
- Bloodwise
- Bloodwise Specialist Programme Grant no. 18007
This publication has 33 references indexed in Scilit:
- The expanding clinical phenotype of germline ABL1 ‐associated congenital heart defects and skeletal malformations syndromeHuman Mutation, 2020
- Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformationsNature Genetics, 2017
- ABL Tyrosine Kinases: Evolution of Function, Regulation, and SpecificityScience Signaling, 2010
- Organization of the SH3-SH2 Unit in Active and Inactive Forms of the c-Abl Tyrosine KinaseMolecular Cell, 2006
- Regulation of the c-Abl and Bcr–Abl tyrosine kinasesNature Reviews Molecular Cell Biology, 2004
- A Myristoyl/Phosphotyrosine Switch Regulates c-AblCell, 2003
- c-Abl Has High Intrinsic Tyrosine Kinase Activity That Is Stimulated by Mutation of the Src Homology 3 Domain and by Autophosphorylation at Two Distinct Regulatory TyrosinesJournal of Biological Chemistry, 2000
- Mice deficient in Abl are osteoporotic and have defects in osteoblast maturationNature Genetics, 2000
- Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogeneCell, 1991
- A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemiaNature, 1982