Biopolym. Cell. 2018; 34(2):107-116.
Biomedicine
Spectrum of mutations in patients with organic acidurias from Ukraine
1, 2Barvinska O. I., 1Olkhovych N. V., 1Shkurko T. O., 2Gorovenko N. G.
  1. National Children's Specialized Hospital Okhmatdyt, Ministry of Health of Ukraine
    28/1, Chornovola Str., Kyiv, Ukraine, 01135
  2. P. L. Shupik National medical academy of post-graduate education
    9, Dorohozhytska Str., Kyiv, Ukraine, 04112

Abstract

Aim. To identify mutations in patients from Ukraine with glutaric aciduria I, isolated methylmalonic aciduria, and isovaleric aciduria. Methods. Sanger sequencing. Results. We have identified 37.5 % of alleles (3/8) in patients with methylmalonic aciduria, 100 % of alleles (4/4) in patients with isovaleric aciduria, 100 % of alleles (4/4) in patients with glutaric aciduria type I. MUT gene mutations in patients from Ukraine are represented by one known N219Y missense mutation p. and a R326G missense rearrangement. Analysis of the GCDH gene in patients from Ukraine revealed three known missense mutations: R383C, G390R and A421V. Rearrangements in the IVD gene of our patients were represented by two novel mutations: 49dupTGTGGCG, S133C, and one known mutation: R53P. Conclusions. The mutations observed in Ukrainian patients with organic acidurias were mostly represented by rare or new rearrangements. These data could be useful for the development of molecular diagnostics of Ukrainian patients with glutaric aciduria I, isolated methylmalonic aciduria, and isovaleric aciduria
Keywords: organic acidurias, MUT, GCDH, IVD

References

[1] Zschocke J. SSIEM Classification of Inborn Errors of Metabolism. In: Blau N, Duran M, Gibson K, Dionisi Vici C. Eds Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Berlin, Heidelberg: “Springer” 2014 817-30.
[2] Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child. 2006;91(11):896-9.
[3] Vaidyanathan K, Narayanan MP, Vasudevan DM. Organic acidurias: an updated review. Indian J Clin Biochem. 2011;26(4):319-25.
[4] Couce ML, Aldamiz-Echevarría L, Bueno MA, Barros P, Belanger-Quintana A, Blasco J, García-Silva MT, Márquez-Armenteros AM, Vitoria I, Vives I, Navarrete R, Fernández-Marmiesse A, Pérez B, Pérez-Cerdá C. Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia. J Hum Genet. 2017;62(3):355-360.
[5] Mushimoto Y, Fukuda S, Hasegawa Y, Kobayashi H, Purevsuren J, Li H, Taketani T, Yamaguchi S. Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab. 2011;102(3):343-8.
[6] Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, Adams J. Current status of newborn screening worldwide: 2015. Semin Perinatol. 2015;39(3):171-87. Review.
[7] Kurkina MV, Baydakova GV, Zakharova EY. Molecular and biochemical characteristics of the isolated methylmalonic aciduria in Russian patients. Med Gen. 2016;15(9):17–28.
[8] Forny P, Schnellmann AS, Buerer C, Lutz S, Fowler B, Froese DS, Baumgartner MR. Molecular Genetic Characterization of 151 Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT. Hum Mutat. 2016;37(8):745-54.
[9] Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW. Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. J Biol Chem. 2010;285(49):38204-13.
[10] Tiffany KA, Roberts DL, Wang M, Paschke R, Mohsen AW, Vockley J, Kim JJ. Structure of human isovaleryl-CoA dehydrogenase at 2.6 A resolution: structural basis for substrate specificity,. Biochemistry. 1997;36(28):8455-64.
[11] den Dunnen JT. Sequence Variant Descriptions: HGVS Nomenclature and Mutalyzer. Curr Protoc Hum Genet. 2016;90:7.13.1-7.13.19.
[12] Acquaviva C, Benoist JF, Callebaut I, Guffon N, Ogier de Baulny H, Touati G, Aydin A, Porquet D, Elion J. N219Y, a new frequent mutation among mut(degree) forms of methylmalonic acidemia in Caucasian patients. Eur J Hum Genet. 2001;9(8):577-82.
[13] Goodman SI, Stein DE, Schlesinger S, Christensen E, Schwartz M, Greenberg CR, Elpeleg ON. Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Hum Mutat. 1998;12(3):141-4.
[14] Anikster Y, Shaag A, Joseph A, Mandel H, Ben-Zeev B, Christensen E, Elpeleg ON. Glutaric aciduria type I in the Arab and Jewish communities in Israel. Am J Hum Genet. 1996;59(5):1012-8.
[15] Biery BJ, Stein DE, Morton DH, Goodman SI. Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish. Am J Hum Genet. 1996;59(5):1006-11.
[16] Mohsen AW, Anderson BD, Volchenboum SL, Battaile KP, Tiffany K, Roberts D, Kim JJ, Vockley J. Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia. Biochemistry. 1998;37(28):10325-35.
[17] Busquets C, Merinero B, Christensen E, Gelpí JL, Campistol J, Pineda M, Fernández-Alvarez E, Prats JM, Sans A, Arteaga R, Martí M, Campos J, Martínez-Pardo M, Martínez-Bermejo A, Ruiz-Falcó ML, Vaquerizo J, Orozco M, Ugarte M, Coll MJ, Ribes A. Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct. Pediatr Res. 2000;48(3):315-22.
[18] Fraidakis MJ, Liadinioti C, Stefanis L, Dinopoulos A, Pons R, Papathanassiou M, Garcia-Villoria J, Ribes A. Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation. JIMD Rep. 2015;18:85-92.
[19] Ozgul RK, Karaca M, Kilic M, Kucuk O, Yucel-Yilmaz D, Unal O, Hismi B, Aliefendioglu D, Sivri S, Tokatli A, Coskun T, Dursun A. Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia. Eur J Med Genet. 2014;57(10):596-601.