Maria Kulecka1, Aldona Wierzbicka2, Agnieszka Paziewska1, Michal Mikula3, Andrzej Habior1, Wojciech Janczyk4, Michalina Dabrowska3, Jakub Karczmarski3, Michal Lazniewski5, Krzysztof Ginalski6, Anna Czlonkowska7, Piotr Socha8, Jerzy Ostrowski9. 1. Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw 01-813, Poland. 2. Department of Biochemistry, Radioimmunology and Experimental Medicine, Children's Memorial Health Institute, Warsaw 04-730, Poland. 3. Department of Genetics, Cancer Center-Institute, Warsaw 02-781, Poland. 4. Department of Gastroenterology, Hepatology and Feeding Disorders, Children's Memorial Health Institute, Warsaw 04-730, Poland. 5. Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Warsaw 02-089, Poland; Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw 02-097, Poland. 6. Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Warsaw 02-089, Poland. 7. Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. 8. Department of Gastroenterology, Hepatology and Feeding Disorders, Children's Memorial Health Institute, Warsaw 04-730, Poland. Electronic address: p.socha@czd.pl. 9. Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw 01-813, Poland; Department of Genetics, Cancer Center-Institute, Warsaw 02-781, Poland. Electronic address: jostrow@warman.com.pl.
Abstract
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. LAY SUMMARY: Higher 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.
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 GOT1p.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. LAY SUMMARY: Higher 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.
Authors: Joao G N Moraes; Susanta K Behura; Jeanette V Bishop; Thomas R Hansen; Thomas W Geary; Thomas E Spencer Journal: Biol Reprod Date: 2020-03-13 Impact factor: 4.285