Abstract
Background: Hereditary tyrosinemia (HT1) is an autosomal recessive disorder characterized by impaired tyrosine catabolism because of fumarylacetoacetate hydrolase deficiency. HT1 is caused by homozygous or compound heterozygous mutations in the FAH gene. The HT1 frequency worldwide is 1:100,000–1:120,000 live births. The frequency of HT1 in the Russian Federation is unknown.
Aim: To estimate the spectrum of mutations in HT1 in several ethnic groups of the Russian Federation.
Materials and methods: From 2004 to 2017, 43 patients were diagnosed with HT1. The analysis of amino acids and succinylacetone was performed using NeoGram Amino Acids and Acylcarnitines Tandem Mass Spectrometry Kit and a Sciex QTrap 3200 quadrupole tandem mass spectrometer. Bi-directional DNA sequence analysis was performed on PCR products using an ABI Prism 3500.
Results: In the Russian Federation, the most common mutation associated with HT1 (32.5% of all mutant alleles) is c.1025C>T (p.Pro342Leu), which is typical for the Chechen ethnic group. Patients of the Yakut, the Buryat, and the Nenets origins had a homozygous mutation c.1090G>C (p.Glu364Gln). High frequency of these ethnicity-specific mutations is most likely due to the founder effect. In patients from Central Russia, the splicing site mutations c.554-1G>T and c.1062+5G>A were the most prevalent, which is similar to the data obtained in the Eastern and Central Europe countries.
Conclusion: There are ethnic specificities in the spectrum of mutations in the FAH gene in HT1. The Chechen Republic has one of the highest prevalence of HT1 in the world.
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Communicated by: Piero Rinaldo, MD, PhD
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Galina Baydakova, Tatiana Ivanova, Svetlana Mikhaylova, Djamila Saydaeva, Laura Dzhudinova, Ayashat Akhlakova, Amina Gamzatova, Igor Bychkov, and Ekaterina Zakharova declare that they have no conflict of interest.
This study was partially granted by SOBI.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
This article does not contain any studies with human or animal subjects performed by the any of the authors.
Baydakova G. V. performed the analysis of amino acids and succinylacetone in spots of dried blood, conducted DNA diagnostics to detect mutations in the FAH gene, calculated the frequency of the disorder, and calculated the confidence interval for frequencies.
Ivanova T. A. performed the analysis of amino acids and succinylacetone in spots of dried blood and conducted DNA diagnostics to detect mutations in the FAH gene.
Mikhaylova S. V. carried out a sample of patients on the territory of the Russian Federation and selection and search of articles and literature.
Saydaeva D. Kh. and Dzhudinova L. L. carried out a sample of patients on the territory of the Chechen Republic and selection and search of articles and literature.
Akhlakova A. I. and Gamzatova A. I. carried out a sample of patients on the territory of the Republic of Dagestan and selection and search of articles and literature.
Bychkov I. O. conducted DNA diagnostics to detect mutations in the FAH gene.
Zakharova E. Yu is the guarantor of the research.
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Baydakova, G.V. et al. (2018). The Unique Spectrum of Mutations in Patients with Hereditary Tyrosinemia Type 1 in Different Regions of the Russian Federation. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 45. JIMD Reports, vol 45. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_144
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DOI: https://doi.org/10.1007/8904_2018_144
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