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

作者：Kulecka Maria; Wierzbicka Aldona; Paziewska Agnieszka; Mikula Michal; Habior Andrzej; Janczyk Wojciech; Dabrowska Michalina; Karczmarski Jakub; Lazniewski Michal; Ginalski Krzysztof; Czlonkowska Anna; Socha Piotr^*; Ostrowski Jerzy^*

来源：Journal of Hepatology, 2017, 67(5): 1026-1030.

DOI：10.1016/j.jhep.2017.07.003

• Macro-AST
• Exome sequencing
• GOT1

Background & Aims: 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.
Methods: 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.
Results: 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.
Conclusions: Our data highlight that testing for the p.Gln208Glu genetic variant may be useful in diagnosis of macro-AST.

• 出版日期2017-11