title: RNF213 Rare Variants in Slovakian and Czech Moyamoya Disease Patients.
abstract: RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients.
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, 6068501 Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Neurology, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Brozman
authors.affiliation: Center of Medical Genetics, Frýdek-Místek, 370 08 Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kyselová
authors.affiliation: Department of Neurology, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Daša
authors.initials: D
authors.lastname: Viszlayová
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, 6068501 Japan.|Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, 6068507 Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Morimoto
authors.affiliation: Department of Neurology, Comprehensive Stroke Center, Ostrava University Faculty of Medicine and University Hospital, Ostrava-Poruba, 708 52 Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Roubec
authors.affiliation: Center for Research and Science, Department of Nursing, Faculty of Health Science, Palacký University, Olomouc, 77515 Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Školoudík
authors.affiliation: Department of Neurology, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Petrovičová
authors.affiliation: Department of Radiology, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Dominik
authors.initials: D
authors.lastname: Juskanič
authors.affiliation: Department of Radiology, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Strauss
authors.affiliation: Department of Radiology, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Marián
authors.initials: M
authors.lastname: Halaj
authors.affiliation: Cardio Center, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kurray
authors.affiliation: Cardio Center, Faculty Hospital Nitra, Constantine Philosopher University, Nitra, 94901 Slovakia.
authors.forename: Marián
authors.initials: M
authors.lastname: Hranai
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, 6068501 Japan.
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, 6068501 Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Laboratory of Nutritional Sciences, Department of Food Science and Nutrition, Mukogawa Women's University, Nishinomiya, 6638121 Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Laboratory of Nutritional Sciences, Department of Food Science and Nutrition, Mukogawa Women's University, Nishinomiya, 6638121 Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Habu
authors.affiliation: Department of Neurology, Comprehensive Stroke Center, Charles University Faculty of Medicine and University Hospital, Hradec Králové, 500 38 Czech Republic.
authors.forename: Roman
authors.initials: R
authors.lastname: Herzig
authors.affiliation: Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Kyoto, 6068501 Japan.
authors.forename: Shohab
authors.initials: S
authors.lastname: Youssefian
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, 6068501 Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D002465:Cell Movement; D002648:Child; D018153:Czech Republic; D005091:Exons; D005260:Female; D005838:Genotype; D006239:Haplotypes; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D018154:Slovakia; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases