Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Ren Fail. 2024 Dec;46(2):2417743. doi: 10.1080/0886022X.2024.2417743. Epub 2024 Oct 24.
Primary hyperoxaluria type 2 (PH2) is a rare disorder caused by mutations. Research on the mutation spectrum and pedigree of PH2 helps in comprehending its pathogenesis and clinical outcomes, guiding clinical diagnosis and treatment.
We report a case of PH2 with a three-generational pedigree. The genotypes of the family members were confirmed by Sanger sequencing. Urine and blood samples were collected for biochemical analysis. Computational analysis was performed to assess the pathogenicity of the mutations. Cellular experiments based on site-directed mutagenesis were conducted to confirm the effect of mutations on GRHPR expression, activity, and subcellular localization.
The proband underwent her first kidney transplantation in 2015, and experienced recurrent urinary tract infections and urolithiasis postoperatively. Graft failure occurred in 2018. Whole exome sequencing identified compound heterozygous mutations p.G160E/p.P203Rfs7. The patient underwent a second kidney transplantation in 2019 and maintained good graft function with urine dilution measures. Notably, her brother and sister carried the same mutations; however, only the proband progressed to renal failure. Computational analysis suggested that p.G160E reduced the affinity of GRHPR for coenzymes. Cellular experiments indicated that p.G160E reduced GRHPR activity (< 0.001), whereas p.P203Rfs7 not only suppressed expression (< 0.001) and reduced activity (< 0.001), but also facilitated protein aggregation. Based on our results, the variant p.G160E was classified as 'pathogenic' according to ACMG guidelines.
Our findings suggest that treatment strategies for the long-term prevention of oxalate nephropathy should be developed for patients with PH2 receiving isolated kidney transplantation. Moreover, the pathogenicity of the compound heterozygous mutations p.G160E/p.P203Rfs*7 was also validated.
2 型原发性高草酸尿症（PH2）是一种由基因突变引起的罕见疾病。研究 PH2 的突变谱和家系有助于理解其发病机制和临床转归，指导临床诊断和治疗。
我们报告了一例具有三代家系的 PH2 病例。通过 Sanger 测序确定了家族成员的基因型。采集尿液和血液样本进行生化分析。进行计算分析以评估突变的致病性。基于定点诱变的细胞实验证实了突变对 GRHPR 表达、活性和亚细胞定位的影响。
先证者于 2015 年首次接受肾脏移植，术后反复发生尿路感染和尿路结石。2018 年移植肾功能衰竭。全外显子组测序发现复合杂合突变 p.G160E/p.P203Rfs7。先证者于 2019 年再次接受肾脏移植，并通过尿液稀释措施维持良好的移植物功能。值得注意的是，她的哥哥和姐姐携带相同的突变，但只有先证者进展为肾衰竭。计算分析表明 p.G160E 降低了 GRHPR 对辅酶的亲和力。细胞实验表明，p.G160E 降低了 GRHPR 活性（<0.001），而 p.P203Rfs7 不仅抑制了表达（<0.001）和活性（<0.001），还促进了蛋白质聚集。根据我们的结果，根据 ACMG 指南，变体 p.G160E 被归类为“致病性”。
我们的研究结果表明，对于接受孤立肾脏移植的 PH2 患者，应制定长期预防草酸肾病的治疗策略。此外，还验证了复合杂合突变 p.G160E/p.P203Rfs*7 的致病性。
