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.
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DOI：
10.1038/s41431-020-00766-w
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Douglas AGL
中科院分区：
文献类型：
--
作者：
Blakes AJM;Gaul E;Lam W;Shannon N;Knapp KM;Bicknell LS;Jackson MR;Wade EM;Robertson S;White SM;Heller R;Chase A;Baralle D;Douglas AGL
ABL 1是一种编码非受体酪氨酸激酶的原癌基因，在与慢性髓性白血病相关的体细胞BCR-ABL融合基因中最为人所知。最近，ABL 1的种系错义变异被发现导致常染色体显性发育综合征，包括先天性心脏病、骨骼畸形和特征性面容。在这里，我们描述了一系列的六个新的不相关的个人与杂合错义变异ABL 1（包括四个新的变体）通过全外显子组测序确定。本系列中所有受影响的个体都概括了ABL 1发育综合征的表型，此外，我们确认听力障碍是该疾病的共同特征。其中四种变体聚集在ABL 1的肉豆蔻酰结合口袋中，这是一个对激酶结构域的自抑制调节至关重要的区域。生物信息学分析的转录全保守性和种系/体细胞变异表明，这个口袋区域是受高错义约束和进化保守。通过用变体ABL 1质粒构建体瞬时转染HEK 293 T细胞来研究ABL 1激酶活性的体外功能性工作显示，与野生型相比，ABL 1特异性底物的磷酸化增加。伊马替尼治疗可抑制酪氨酸激酶活性的增加。这一病例系列的6例新的患者与种系杂合ABL 1错义变异进一步描绘了这种情况的表型谱，并认识到小头畸形是一种常见的发现。我们的分析支持ABL 1的功能获得机制，由于失去自抑制，并证明了潜在的药理学抑制使用伊马替尼。
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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影响因子：
1.6
作者：
Bravo-Gil, Nereida;Marcos, Irene;Borrego, Salud
通讯作者：
Borrego, Salud
影响因子：
2
作者：
Knapp, Karen M.;Poke, Gemma;Bicknell, Louise S.
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Bicknell, Louise S.
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
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Ng, Pauline C.
影响因子：
7.3
作者：
Colicelli J
通讯作者：
Colicelli J
影响因子：
7
作者：
Traynelis, Joshua;Silk, Michael;Petrovski, Slave
通讯作者：
Petrovski, Slave