Possible genetic imitator of Wilsons disease phenotype 23336

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Possible genetic imitator of Wilson’s disease phenotype 23336 Agnese Zarina 1, 2*, Dmitrijs Rots

Possible genetic imitator of Wilson’s disease phenotype 23336 Agnese Zarina 1, 2*, Dmitrijs Rots 1, Madara Kreile 1, 2, Ieva Tolmane 3, 4, Gunta Cernevska 5, Ieva Pukite 5, Zita Krumina 2, 5, Linda Gailite 1 1 Rīga Stradiņš University, Scientific Laboratory of Molecular Genetics, 16 Dzirciema street, Riga, Latvia 2 Rīga Stradiņš University, Department of Biology and Microbiology, 16 Dzirciema street, Riga, Latvia 3 Riga East Clinical University Hospital, stationary “Infectology Center of Latvia”, 3 Linezera street, Riga, Latvia 4 University of Latvia, Faculty of Medicine, 19 Raina boulevard, Riga, Latvia 5 Children Clinical university Hospital, 45 Vienibas avenue, Riga, Latvia *Corresponding author, e-mail: agnese. [email protected] lv Introduction Results Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in gene ATP 7 B. Although WD has strict diagnostic criteria, some of WD clinically suspected cases fail to be confirmed molecularly – no pathogenic variants are found in the ATP 7 B gene, leading to the assumption about influence of other genes to the WD-like phenotype. One of the candidate genes is ceruloplasmin encoding gene CP. Ceruloplasmin binds and transports copper by interacting with ATP 7 B (see figure 1). Both variants had statistically significant differences between analysed groups – rs 66508328 variant AA genotype and rs 11708215 variant GG genotype were more common among the patients with only clinically confirmed WD (2/10 vs 0/49 for rs 66508328; p=0. 03061; and 2/10 vs 0/48 for rs 11708215). Two patients from only clinically confirmed WD patient group having previously mentioned genotypes experienced the neurological form of WD. Table 1. Association of CP gene promoter variants with WD phenotype and ATP 7 B genotype. Inheritance model rs 66508328 Figure 1. A schematic illustration of copper transport and metabolism (F. Wu et al. “Wilson’s disease: a comprehensive review of the molecular mechanisms. , ” Int. J. Mol. Sci. , 2015, 16(3): 6419– 31. Aim of the project To clarify the possible association of WD phenotype and ATP 7 B gene variants with CP gene promoter variants. Materials and methods Study included 51 unrelated patients with clinically confirmed Wilson disease. ATP 7 B gene and CP gene genotypes were ascertained (see in figure 2). For statistical analysis „PLINK 1. 07” software was used analysing for inheritance model. ATP 7 B genotype PCR-Bi. PASA Direct sequencing MLPA CP gene promoter genotype (direct sequencing) rs 66508328 rs 11708215 rs 66508328 rs 11708215 Genotype (AA/AG/GG) Allelic (A/G) Dominant (AA+AG/GG) Recessive (AA/AG+GG) Genotype (GG/GA/AA) Allelic (G/A) Dominant (GG+GA/AA) Recessive (GG/GA+AA) Neurological Hepatologsymptoms ical n=8 symptoms n=41 p value 0/1/7 0/6/35 1 1/15 1/7 6/76 6/35 1 1 0/8 0/41 1 0/2/6 0/15/25 0. 6938 2/14 2/6 15/65 15/25 0. 4998 0. 7290 0/8 0/40 0. 6938 Non-WD* n=12 2/0/10 WD** n=49 0/7/42 4/20 2/10 7/91 7/42 0. 2240 1 2/10 0/49 0. 0361 2/0/10 0/17/31 0. 0016 4/20 2/10 17/79 17/31 1 0. 3059 2/10 0/48 0. 0373 0. 0289 *Non-WD – patients without two pathogenic variants found in ATP 7 B gene; **WD - patients with two pathogenic variants found in ATP 7 B gene rs 11708215 Conclusions Phenotype – genotype analysis Group 1. Patients with clinically and molecularly confirmed WD (n=49) Group 2. Patients with only clinically confirmed WD (n=12). Figure 2. Methods used in the study. CP gene different variants contribute to WD-like phenotype in clinically confirmed WD patients with neurological symptoms and without pathogenic variants in ATP 7 B gene, but for a confirmation a larger study group is required