Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect

Background: A gain-of-function mutation in germline ABL1 causes a syndrome including congenital heart defects. However, the molecular mechanisms of this syndrome remain unknown. In this study, we found a novel ABL1 mutation in a Japanese family with ventricular septal defect, finger contracture, skin abnormalities and failure to thrive, and the molecular mechanisms of these phenotypes were investigated. Methods and results: Whole-exome sequencing on several family members revealed a novel mutation (c.1522A > C, p.15080 in the tyrosine kinase domain of ABLI, and complete co-segregation with clinical presentations was confirmed in all members. Wild-type and mutant ABL1 were transfected into human embryonic kidney 293 cells for functional analysis. Western blotting confirmed that tyrosine phosphorylation in STATS, a substrate of ABL1, was enhanced, and the novel mutation was proved to be a gain-of-function mutation. Since this novel mutation in ABL1 enhances tyrosine kinase activity, phosphorylated proteorne analysis was used to elucidate the molecular pathology. The proteorne analysis showed that phosphorylation in proteins such as UFD1, AX1N1, ATRX, which may be involved in the phenotypes, was enhanced in the mutant group. Conclusions: The onset of congenital heart defects associated with this syndrome appears to involve a mechanism caused by UFD1 common to 22q.11.2 deletion syndrome. On the other hand, AX1N1 and ATRX may be important in elucidating the mechanisms of other phenotypes, such as finger contracture and failure to thrive. Verification of these hypotheses would lead to further understanding of the pathophysiology and the development of treatment methods. (C) 2020 Elsevier B.V. All rights reserved.

Automated summary

This study identified a novel ABL1 gene mutation causing a syndrome with congenital heart defects, finger contracture, skin abnormalities, and failure to thrive. Functional analysis and phosphorylated proteorne analysis confirmed the impact of the mutation on ABL1 activity and highlighted potential proteins involved in the disease phenotypes. Further research on the molecular mechanisms could provide insights for understanding the pathophysiology and developing treatment methods.