1] Medical Genetics Unit, San Luigi University Hospital, Orbassano, Torino, Italy [2] University of Torino, Department Clinical and Biological Sciences, Torino, Italy.
Division of Nephrology, Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.
Kidney Int. 2014 Dec;86(6):1197-204. doi: 10.1038/ki.2014.222. Epub 2014 Jul 2.
Primary hyperoxaluria type 1 displays a heterogeneous phenotype, likely to be affected by genetic and non-genetic factors, including timeliness of diagnosis and quality of care. As previous genotype-phenotype studies were hampered by limited patient numbers the European OxalEurope Consortium was constituted. This preliminary retrospective report is based on 526 patients of which 410 have the AGXT genotype defined. We grouped mutations by the predicted effect as null, missense leading to mistargeting (G170R), and other missense, and analyzed their phenotypic correlations. Median age of end-stage renal disease increased from 9.9 for 88 homozygous null patients, 11.5 for 42 heterozygous null/missense, 16.9 for 116 homozygous missense patients, 25.1 for 61 G170R/null patients, 31.2 for 32 G170R/missense patients, and 33.9 years for 71 homozygous G170R patients. The outcome of some recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an unprecedented number of G170R homozygotes is described in detail. Diagnosis is still delayed and actions aimed at increasing awareness of primary hyperoxaluria type 1 are recommended. Thus, in addition to G170R, other causative mutations are associated with later onset of end-stage renal disease. The OxalEurope registry will provide necessary tools for characterizing those genetic and non-genetic factors through a combination of genetic, functional, and biostatistical approaches.
1 型原发性高草酸尿症表现出异质性表型，可能受到遗传和非遗传因素的影响，包括诊断的及时性和护理质量。由于以前的基因型-表型研究受到患者数量有限的限制，因此成立了欧洲 OxalEurope 联合会。这是一项初步的回顾性报告，基于 526 名患者，其中 410 名患者的 AGXT 基因型已确定。我们根据预测的效果将突变分为无功能、导致靶向错误的错义突变（G170R）和其他错义突变，并分析了它们的表型相关性。终末期肾病的中位年龄从 88 名纯合子无功能突变患者的 9.9 岁、42 名杂合子无功能/错义突变患者的 11.5 岁、116 名纯合子错义突变患者的 16.9 岁、61 名 G170R/无功能突变患者的 25.1 岁、32 名 G170R/错义突变患者的 31.2 岁和 71 名纯合子 G170R 患者的 33.9 岁增加。详细描述了一些常见的错义突变（p.I244T、p.F152I、p.M195R、p.D201E、p.S81L、p.R36C）和前所未有的 G170R 纯合子的结果。诊断仍然延迟，建议采取行动提高对 1 型原发性高草酸尿症的认识。因此，除了 G170R，其他致病突变也与终末期肾病的发病时间较晚有关。OxalEurope 登记处将通过遗传、功能和生物统计学方法的组合，提供必要的工具来描述这些遗传和非遗传因素。
