家族性青少年高尿酸血症肾病家系患者尿调节素编码基因突变位点研究

A pedigree research on mutation sites of the uromodulin-encoding gene from a patient with familial juvenile hyperuricemic nephropathy

目的本文报道家族性青少年高尿酸血症肾病（FJHN）一家系的尿调节素（UMOD）编码基因新的位点突变并结合文献复习,以期引起肾脏病学者对该病的足够重视。方法收集、核实和整理分析1例FJHN先证者的临床特征、实验室检查及该家系其他成员相关的临床资料;检测先证者及其长子和外甥的UMOD编码基因外显子2~5变异情况。结果先证者呈现典型的FJHN临床表现,包括青年发病,显著性高尿酸血症、痛风性关节炎和痛风石,早期即有夜尿增多等尿浓缩功能减退的表现,肾功能损害持续缓慢进展,至40岁左右时发展为终末期肾病。家系调查及基因突变检测显示,家系三代中至少有高尿酸血症12人,其中3人已死于尿毒症,先证者也已进入尿毒症期,并正在接受血液透析治疗。先证者及其长子经基因检测均有相同的基因突变：UMOD编码基因位第4外显子上第854碱基出现C/A嵌合子（正常参考基因碱基为C）变异,使氨基酸序列第285位丙氨酸（A,GCG）变异为谷氨酸（E,GAG）。无高尿酸血症的先证者外甥经基因检测未发现基因外显子2~5变异。结论家族性青少年高尿酸血症肾病可能与UMOD编码基因位第4外显子上第854碱基变异（此为一新发现的基因突变）有关,对有显著高尿酸血症、痛风,尤其是有慢性肾脏病家族史的青（少）壮年患者,应考虑有无FJHN的可能性,通过医学影像学、肾活检和（或）UMOD基因的检测,尽早明确诊断、避免误诊、漏诊。

Objective To draw enough attention from nephrologists to familial juvenile hyperuricemie nephropathy （FJHN） , this paper reported a case with FJHN presented by a novel mutation of uromodulin （UMOD） gene from the proband, his oldest son, and his nephew, together with literature review. Methods Clinical manifestations and laboratory data of the proband were collected and analyzed. Mutations of exon 2-5 of UMOD-encoding gene of proband, his eldest son, and nephew were measured. Meanwhile, clinical relevant data of other members of the family were collected, validated, and analyzed. Results The proband presented with typical clinical features of FJHN, including juvenile onset, obvious hyperuricemia, gout arthritis, gout stone, early increased noeturia and other manifestations indicating decrease of urinary concentration function, continuous and slow progression of renal function damage, and occurrence of end- stage renal disease at the age of about 40 years. Pedigree investigation showed that at least 12 members within three generations of the family suffered from hyperuricemia, 3 of whom died of uremia, and the proband was also suffering from uremia and receiving hemodialysis. Gene measuring showed that the probaud and his eldest son had the same genetic mutation： a novel sense heterozygous chimerical mutation at the 4th exon of UMOD- coding gene was identified in the proband and his eldest son, so that, in the amino acid sequence, the 285th alanine （A, GCG） changed to glutamic acid （E, GAG）, which was a newly discovered gene mutation. His nephew without hyperuricemia had no mutation on exon 2-5. Conclusion FJHN is an autosomal dominant disorder. If an adolescent has symptoms of remarkable hyperuricemia, gout, and a family history of chronic kidney disease, FJHN should be considered, and need to be recognized through medical imaging, renal biopsy, and UMOD gene mutation test, so that early correct diagnosis of FJHN should be made and misdiagnosis be avoided.