title: Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected].
abstract: β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.
authors: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands, ncu.metabolism@gmail.com.
authors: Yoko
authors: Y
authors: Nakajima
authors: Judith
authors: J
authors: Meijer
authors: Doreen
authors: D
authors: Dobritzsch
authors: Tetsuya
authors: T
authors: Ito
authors: Rutger
authors: R
authors: Meinsma
authors: Nico G G M
authors: NG
authors: Abeling
authors: Jeroen
authors: J
authors: Roelofsen
authors: Lida
authors: L
authors: Zoetekouw
authors: Yoriko
authors: Y
authors: Watanabe
authors: Kyoko
authors: K
authors: Tashiro
authors: Tomoko
authors: T
authors: Lee
authors: Yasuhiro
authors: Y
authors: Takeshima
authors: Hiroshi
authors: H
authors: Mitsubuchi
authors: Akira
authors: A
authors: Yoneyama
authors: Kazuhide
authors: K
authors: Ohta
authors: Kaoru
authors: K
authors: Eto
authors: Kayoko
authors: K
authors: Saito
authors: Tomiko
authors: T
authors: Kuhara
authors: André B P
authors: AB
authors: van Kuilenburg
mesh_terms: D000015:Abnormalities, Multiple / Q000453:epidemiology* / Q000235:genetics*; D000483:Alleles; D000581:Amidohydrolases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D001927:Brain Diseases / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan / Q000453:epidemiology; D008297:Male; D008958:Models, Molecular; D009069:Movement Disorders / Q000453:epidemiology* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009422:Nervous System Diseases / Q000209:etiology / Q000235:genetics; D010641:Phenotype; D015995:Prevalence; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000453:epidemiology* / Q000235:genetics*
chemical_list: D000581:Amidohydrolases; C021590:beta-ureidopropionase