A heterozygous mutation in GOT1 is associated with familial macro-aspartate aminotransferase

Macro-aspartate aminotransferase (macro-AST) is a rare, benign condition without a previously confirmed genetic basis. Macro-AST manifests as persistent elevation of AST levels, due to association of the protein with immunoglobulins in the circulation. Here, we report a missense variant (p.Gln208Glu, rs374966349) in glutamate oxaloacetate transaminase 1 (GOT1), as a putative causal variant predisposing to familial macro-AST. Using exome sequencing and genotyping, the GOT1 p.Gln208Glu mutation was detected in 47 (53.4%) of 88 probands from 20 of 28 (71%) families, while its prevalence in 1644 healthy controls was only 0.18%. In silico modeling demonstrated that the amino acid at this position is not conserved among different species and that, functionally, a negatively charged glutamate on the GOT1 surface could strongly anchor serum immunoglobulins. Our data highlight that testing for this genetic variant may be useful in diagnosis of macro-AST.