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Loss of function mutation in glutamic pyruvate transaminase 2 ( GPT2 ) causes developmental encephalopathy
Author(s) -
Celis Katrina,
Shuldiner Scott,
Haverfield Eden V.,
Cappell Joshua,
Yang Rongze,
Gong DaWei,
Chung Wendy K.
Publication year - 2015
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-015-9824-x
Subject(s) - biology , genetics , transamination , mutation , transaminase , missense mutation , encephalopathy , gene , biochemistry , medicine , amino acid , enzyme
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.