A heterozygous mutation in GOT1 is associated with familial macro-aspartate aminotransferase
Authors: Maria Kulecka, Aldona Wierzbicka, Agnieszka Paziewska, Michal Mikula, Andrzej Habior, Wojciech Janczyk, Michalina Dabrowska, Jakub Karczmarski, Michal Lazniewski, Krzysztof Ginalski, Anna Czlonkowska, Piotr Socha, Jerzy Ostrowski
Journal: Journal of Hepatology (2017)

•Individuals with macro-AST demonstrate fluctuating, not persistent, elevation of AST levels in blood.•The causative gene of macro-AST has not yet been identified.•A genetic variant associated with macro-AST was found in theGOT1 gene.•Testing for this variant could aid diagnosis of macro-AST. Background & AimsMacro-aspartate aminotransferase (macro-AST) manifests as a persistent elevation of AST levels, because of association of the protein with immunoglobulins in the circulation. Macro-AST is a rare, benign condition without a previously confirmed genetic basis.MethodsWhole exome sequencing (WES)-based screening was performed on 32 participants with suspected familial macro-AST, while validation of variants was performed on an extended cohort of 92 probands and 1,644 healthy controls using Taqman genotyping.ResultsA missense variant (p.Gln208Glu, rs374966349) in glutamate oxaloacetate transaminase 1 (GOT1) was found, as a putative causal variant predisposing to familial macro-AST. The GOT1 p.Gln208Glu mutation was detected in 50 (54.3%) of 92 probands from 20 of 29 (69%) families, while its prevalence in healthy controls was only 0.18%. In silico analysis 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.ConclusionsOur data highlight that testing for the p.Gln208Glu genetic variant may be useful in diagnosis of macro-AST.Lay summaryHigher than normal levels of aspartate aminotransferase (AST) in the bloodstream may be a sign of a health problem. Individuals with macro-AST have elevated blood AST levels, without ongoing disease and often undergo unnecessary medical tests before the diagnosis of macro-AST is established. We found a genetic variant in the GOT1 gene associated with macro-AST. Genetic testing for this variant may aid diagnosis of macro-AST. Macro-aspartate aminotransferase (macro-AST) manifests as a persistent elevation of AST levels, because of association of the protein with immunoglobulins in the circulation. Macro-AST is a rare, benign condition without a previously confirmed genetic basis. Whole exome sequencing (WES)-based screening was performed on 32 participants with suspected familial macro-AST, while validation of variants was performed on an extended cohort of 92 probands and 1,644 healthy controls using Taqman genotyping. A missense variant (p.Gln208Glu, rs374966349) in glutamate oxaloacetate transaminase 1 (GOT1) was found, as a putative causal variant predisposing to familial macro-AST. The GOT1 p.Gln208Glu mutation was detected in 50 (54.3%) of 92 probands from 20 of 29 (69%) families, while its prevalence in healthy controls was only 0.18%. In silico analysis 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 the p.Gln208Glu genetic variant may be useful in diagnosis of macro-AST.