Fig. 4: Missense variants cause increased ABL1 tyrosine kinase activity in vitro. | European Journal of Human Genetics

Fig. 4: Missense variants cause increased ABL1 tyrosine kinase activity in vitro.

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

Fig. 4

a Tyrosine kinase activity of ABL1 missense constructs. Missense variants NM_007313.2:c.1066G > A p.(Ala356Thr), c.1354G > A p.(Ala452Thr), c.1574T > C p.(Val525Ala), and c.1582G > A p.(Glu528Lys) markedly increase the phosphorylation of ABL1 at residue Tyr245, and the phosphorylation of the ABL1-specific substrate STAT5B, compared to wild-type. The c.881A > G p.(Glu294Gly) construct (for which the variant is not thought to be deleterious), does not increase phosphorylation of ABL1 or STAT5B. The c.731T > C p.(Val244Ala) construct increased phosphorylation of STAT5B and tyrosine phosphorylation overall, but not at ABL1-Tyr245. Substitution of Val244 for alanine therefore appears to result in loss of phosphorylation of the adjacent Tyr245 residue. These findings are consistent with gain of ABL1 tyrosine kinase activity due to loss of auto-inhibition through myristoyl binding. b Treatment with 1 µM imatinib results in complete loss of phosphorylation activity.

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