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Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity

Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity
Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity
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.
1018-4813
1-11
Blakes, Alexander J M
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Gaul, Emily
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Lam, Wayne
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Shannon, Nora
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Knapp, Karen M
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Bicknell, Louise S.
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Jacxkson, Meremaihi R
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Wade, Emma M
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Robertson, Stephen
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White, Susan M.
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Heller, Raoul
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Chase, Andrew
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Baralle, Diana
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Douglas, Andrew
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Blakes, Alexander J M
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Gaul, Emily
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Lam, Wayne
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Shannon, Nora
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Knapp, Karen M
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Bicknell, Louise S.
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Jacxkson, Meremaihi R
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Wade, Emma M
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Robertson, Stephen
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White, Susan M.
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Heller, Raoul
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Chase, Andrew
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Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Douglas, Andrew
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Blakes, Alexander J M, Gaul, Emily, Lam, Wayne, Shannon, Nora, Knapp, Karen M, Bicknell, Louise S., Jacxkson, Meremaihi R, Wade, Emma M, Robertson, Stephen, White, Susan M., Heller, Raoul, Chase, Andrew, Baralle, Diana and Douglas, Andrew (2020) Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity. European Journal of Human Genetics, 1-11. (doi:10.1038/s41431-020-00766-w).

Record type: Article

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.

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Accepted/In Press date: 29 October 2020
e-pub ahead of print date: 22 November 2020

Identifiers

Local EPrints ID: 445253
URI: http://eprints.soton.ac.uk/id/eprint/445253
ISSN: 1018-4813
PURE UUID: 3835670e-04af-41ec-9abf-b8e1e3938898
ORCID for Andrew Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for Andrew Douglas: ORCID iD orcid.org/0000-0001-5154-6714

Catalogue record

Date deposited: 26 Nov 2020 17:31
Last modified: 26 Nov 2021 05:39

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Contributors

Author: Alexander J M Blakes
Author: Emily Gaul
Author: Wayne Lam
Author: Nora Shannon
Author: Karen M Knapp
Author: Louise S. Bicknell
Author: Meremaihi R Jacxkson
Author: Emma M Wade
Author: Stephen Robertson
Author: Susan M. White
Author: Raoul Heller
Author: Andrew Chase ORCID iD
Author: Diana Baralle ORCID iD
Author: Andrew Douglas ORCID iD

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