Primary Hyperoxaluria Type III Gene HOGA1 (Formerly DHDPSL) as a Possible Risk Factor for Idiopathic Calcium Oxalate Urolithiasis
Primary Hyperoxaluria Type III Gene HOGA1 (Formerly DHDPSL) as a Possible Risk Factor for Idiopathic Calcium Oxalate Urolithiasis
复制标题
DOI：
10.2215/cjn.02760311
复制
发表时间：
2011-09-01
影响因子：
9.8
通讯作者：
Milliner, Dawn S.
中科院分区：
文献类型：
--
作者：
Monico, Carla G.;Rossetti, Sandro;Milliner, Dawn S.
背景和目的：原发性高草酸尿症I型和II型(PHI和PHII)是导致高草酸尿症和草酸钙尿石症的罕见单基因病因。最近，我们描述了III型，由于HOGA1(以前的DHDPSL)突变，假设导致线粒体4-羟基-2-氧代戊二酸醛缩酶活性增加，导致草酸过量。设计、设置、参与者和测量为了进一步探索HOGA1的病理生理学，我们筛查了额外的非PHI-PHII患者并进行了逆转录聚合酶链式反应分析。假设HOGA1可能影响尿草酸，我们还筛查了100例特发性草酸钙结石患者。结果在28例非PHI、PHII或任何可识别的次要原因导致的明显高草酸尿症患者中，我们发现10例(36%)有两个HOGA1突变(4个新突变，包括一个无意义变异)。终止密码子和两个常见突变的逆转录聚合酶链式反应显示稳定表达。从新的和我们之前描述的PHIII队列中，确定了25名患者进行研究。尿草酸低于PHI和PHII，尿钙和尿酸高于PHI和PHII。中位随访7.2年，平均EGFR为116ml/min/1.73m(2)。在2例轻度高草酸尿症患者和3例特发性草酸钙结石患者中发现HOGA1杂合子。在166名对照中未检测到HOGA1变异。结论在PHIII常染色体隐性遗传的背景下，这些发现支持HOGA1的功能丧失机制，具有潜在的显性-负效应。在特发性草酸钙尿石症中检测HOGA1变异也表明HOGA1可能是这种情况的一个易感因素。临床J am Soc肾病6：2289-2295,2011。DOI：10.2215/CJN.02760311
Background and objectives Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate.Design, setting, participants, & measurements To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis. Postulating that HOGA1 may influence urine oxalate, we also screened 100 idiopathic calcium oxalate stone formers.Results Of 28 unrelated hyperoxaluric patients with marked hyperoxaluria not due to PHI, PHII, or any identifiable secondary cause, we identified 10 (36%) with two HOGA1 mutations (four novel, including a nonsense variant). Reverse transcription PCR of the stop codon and two common mutations showed stable expression. From the new and our previously described PHIII cohort, 25 patients were identified for study. Urine oxalate was lower and urine calcium and uric acid were higher when compared with PHI and PHII. After 7.2 years median follow-up, mean eGFR was 116 ml/min per 1.73 m(2). HOGA1 heterozygosity was found in two patients with mild hyperoxaluria and in three of 100 idiopathic calcium oxalate stone formers. No HOGA1 variants were detected in 166 controls.Conclusions These findings, in the context of autosomal recessive inheritance for PHIII, support a loss-of-function mechanism for HOGA1, with potential for a dominant-negative effect. Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition. Clin J Am Soc Nephrol 6: 2289-2295, 2011. doi: 10.2215/CJN.02760311