Nakajima Yoko, Meijer Judith, Dobritzsch Doreen, Ito Tetsuya, Meinsma Rutger, Abeling Nico G G M, Roelofsen Jeroen, Zoetekouw Lida, Watanabe Yoriko, Tashiro Kyoko, Lee Tomoko, Takeshima Yasuhiro, Mitsubuchi Hiroshi, Yoneyama Akira, Ohta Kazuhide, Eto Kaoru, Saito Kayoko, Kuhara Tomiko, van Kuilenburg André B P
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands,
J Inherit Metab Dis. 2014 Sep;37(5):801-12. doi: 10.1007/s10545-014-9682-y. Epub 2014 Feb 14.
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.
β-脲基丙酸酶（βUP）缺乏症是一种常染色体隐性疾病，其特征为N-氨甲酰基-β-氨基酸尿症。迄今为止，仅有16例经基因确诊的βUP缺乏症患者的报道。在此，我们报告13例日本βUP缺乏症患者的临床、生化及分子学研究结果。在这组患者中，鉴定出三个新的错义突变（p.G31S、p.E271K和p.I286T）以及一个最近报道的突变（p.R326Q）。在所有13例患者中均检测到p.R326Q突变，其中8例患者为该突变的纯合子。对110名日本人进行p.R326Q突变筛查，结果显示其等位基因频率为0.9%。在HEK293细胞中对突变型βUP酶进行瞬时表达，结果表明p.E271K和p.R326Q突变导致酶活性显著降低（≤1.3%）。相反，含有p.G31S和p.I286T突变的βUP酶分别具有50%和70%的残余活性，这表明我们不能排除UPB1基因非编码区存在其他突变的可能性。对人βUP同源模型进行分析发现，这些突变（p.G31S、p.E271K和p.R326Q）对酶活性的影响很可能与寡聚体组装不当有关。在已确诊患者中观察到从神经系统受累（包括惊厥和自闭症）到无症状等高度可变的表型。p.R326Q在正常日本人群中的高患病率表明，βUP缺乏症并不像通常认为的那样罕见，对于原因不明的神经异常患者，应将βUP缺乏症筛查纳入诊断过程。
