Iwai Naoharu, Mino Yukari, Hosoyamada Makoto, Tago Naomi, Kokubo Yoshihiro, Endou Hitoshi
National Cardiovascular Center, Suita, Osaka, Japan.
Kidney Int. 2004 Sep;66(3):935-44. doi: 10.1111/j.1523-1755.2004.00839.x.
Recently, SLC22A12 has been identified as a urate-anion exchanger in the human kidney.
We screened for polymorphisms of SLC22A12 and conducted an association study between genetic polymorphisms and urate levels in an epidemiologic cohort representing the general population in Japan. Functional significance of mutations was assessed by oocyte expression analysis.
We found five missense, one nonsense, and one deletion mutations [R90H, A226V, R228E, W258Stop, Q312L, D313A (deletion of 313D-333P), and R477H] in 24 subjects with hypouricemia recruited from an epidemiologic cohort (Suita Study) representing the general population in Japan (N= 1875). A statistical analysis indicated that the 90H (N= 14), 477H (N= 5), and 258Stop (hetero + homo N= 82 + 3) alleles were associated with hypouricemia. The alleles 228E and 313A (deletion of 313D-333P) were found just once in the total population. In vitro oocyte expression analysis indicated that 313A (deletion of 313D-333P) had no urate transport activity, indicating that this is a newly identified mutation for idiopathic renal hypouricemia. Intriguingly, the allele frequency of 258Stop was unexpectedly high (2.37%). However, this inactivating mutation does not seem to be harmful in the general population. The effects of common polymorphisms of SLC22A12 were also investigated. Based on linkage disequilibrium, 16 common polymorphisms were categorized into six distinct groups, and six representative genotypes were determined. None of these six common polymorphisms affected the serum uric acid level. A haplotype analysis also suggested that these common genotypes/haplotypes were not important in determining the serum uric acid levels in the general population.
SLC22A12 is a major gene for hypouricemia but not hyperuricemia in Japanese.
最近，SLC22A12被确定为人类肾脏中的尿酸-阴离子交换器。
我们筛选了SLC22A12的多态性，并在一个代表日本普通人群的流行病学队列中进行了基因多态性与尿酸水平之间的关联研究。通过卵母细胞表达分析评估突变的功能意义。
我们在从代表日本普通人群的流行病学队列（吹田研究，N = 1875）中招募的24名低尿酸血症患者中发现了5个错义突变、1个无义突变和1个缺失突变[R90H、A226V、R228E、W258Stop、Q312L、D313A（313D - 333P缺失）和R477H]。统计分析表明，90H（N = 14）、477H（N = 5）和258Stop（杂合+纯合N = 82 + 3）等位基因与低尿酸血症相关。228E和313A（313D - 333P缺失）等位基因在总人群中仅发现一次。体外卵母细胞表达分析表明，313A（313D - 333P缺失）没有尿酸转运活性，表明这是一个新发现的特发性肾性低尿酸血症突变。有趣的是，258Stop的等位基因频率意外地高（2.37%）。然而，这种失活突变在普通人群中似乎并无危害。我们还研究了SLC22A12常见多态性的影响。基于连锁不平衡，16个常见多态性被分为6个不同的组，并确定了6种代表性基因型。这6种常见多态性均未影响血清尿酸水平。单倍型分析也表明，这些常见基因型/单倍型在确定普通人群的血清尿酸水平方面并不重要。
在日本人中，SLC22A12是低尿酸血症而非高尿酸血症的主要基因。
