Alanazi Mohammed, Al-Arfaj Abdulrahman Saud, Abduljaleel Zainularifeen, Fahad Al-Arfaj Hussein, Reddy Parine Narasimha, Purusottapatnam Shaik Jilani, Khan Zahid, Ali Khan Pathan Akbar
Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Medicine, King Saud University Hospital, Riyadh 11426, Saudi Arabia.
Biomed Res Int. 2014;2014:290325. doi: 10.1155/2014/290325. Epub 2014 Jul 9.
Over the past decade, a steady increase in the incidence of HPRT-related hyperuricemia (HRH) has been observed in Saudi Arabia. We examined all the nine exons of HPRT gene for mutations in ten biochemically confirmed hyperuricemia patients, including one female and three normal controls. In all, we identified 13 novel mutations in Saudi Arabian HPRT-related hyperuricemia patients manifesting different levels of uric acid. The Lys103Met alteration was highly recurrent and was observed in 50% of the cases, while Ala160Thr and Lys158Asn substitutions were found in two patients. Moreover, in 70% of the patients ≥2 mutations were detected concurrently in the HPRT gene. Interestingly, one of the patients that harbored Lys103Met substitution along with two frameshift mutations at codons 85 and 160 resulting in shortened protein demonstrated unusually high serum uric acid level of 738 μmol/L. Two of the seven point mutations that resulted in amino acid change (Lys103Met and Val160Gly) were predicted to be damaging by SIFT and Polyphen and were further analyzed for their protein stability and function by molecular dynamics simulation. The identified novel mutations in the HPRT gene may prove useful in the prenatal diagnosis and genetic counseling.
在过去十年中，沙特阿拉伯HPRT相关高尿酸血症（HRH）的发病率呈稳步上升趋势。我们对10例经生化确诊的高尿酸血症患者（包括1名女性和3名正常对照）的HPRT基因的所有9个外显子进行了突变检测。我们共在沙特阿拉伯HPRT相关高尿酸血症患者中鉴定出13个新突变，这些患者表现出不同水平的尿酸。Lys103Met改变高度复发，在50%的病例中观察到，而Ala160Thr和Lys158Asn替代在两名患者中发现。此外，在70%的患者中，HPRT基因同时检测到≥2个突变。有趣的是，其中一名携带Lys103Met替代以及密码子85和160处两个移码突变导致蛋白质缩短的患者，血清尿酸水平异常高，达到738μmol/L。导致氨基酸变化的7个点突变中的两个（Lys103Met和Val160Gly）经SIFT和Polyphen预测具有损害性，并通过分子动力学模拟进一步分析其蛋白质稳定性和功能。在HPRT基因中鉴定出的新突变可能在产前诊断和遗传咨询中有用。
