Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy
Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy
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DOI：
10.1007/s10545-015-9824-x
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发表时间：
2015-09-01
影响因子：
4.2
通讯作者：
Chung, Wendy K.
中科院分区：
文献类型：
--
作者：
Celis, Katrina;Shuldiner, Scott;Chung, Wendy K.
智力残疾是遗传异质性的，很可能许多负责基因尚未被确定。我们描述了三个兄弟姐妹孤立的，严重的发育性脑病。在广泛的无信息遗传和代谢测试后，全外显子组测序鉴定了谷氨酸丙酮酸转氨酶2（GPT 2）或丙氨酸转氨酶2（ALT 2）的纯合新变体，c.459 C > G p.Ser153Arg，其在家族中与发育性脑病分离。所有计算机模拟预测算法都预测该变体具有破坏性。GPT 2是编码ALT 2的基因，ALT 2负责丙氨酸和2-酮戊二酸的可逆转氨作用以形成丙酮酸和谷氨酸。GPT 2在大脑中表达，并在产生谷氨酸（一种兴奋性神经递质）的途径中。重组野生型和突变ALT 2蛋白的功能测定表明p.Ser153Arg突变导致酶功能的严重丧失。我们认为，复发性遗传性功能丧失GPT 2突变是智力残疾的一个新的原因。
Intellectual disability is genetically heterogeneous, and it is likely that many of the responsible genes have not yet been identified. We describe three siblings with isolated, severe developmental encephalopathy. After extensive uninformative genetic and metabolic testing, whole exome sequencing identified a homozygous novel variant in glutamic pyruvate transaminase 2 (GPT2) or alanine transaminase 2 (ALT2), c.459 C > G p.Ser153Arg that segregated with developmental encephalopathy in the family. This variant was predicted to be damaging by all in silico prediction algorithms. GPT2 is the gene encoding ALT2 which is responsible for the reversible transamination of alanine and 2-oxoglutarate to form pyruvate and glutamate. GPT2 is expressed in brain and is in the pathway to generate glutamate, an excitatory neurotransmitter. Functional assays of recombinant wild-type and mutant ALT2 proteins demonstrated the p.Ser153Arg mutation resulted in a severe loss of enzymatic function. We suggest that recessively inherited loss of function GPT2 mutations are a novel cause of intellectual disability.