Warwicker P, Goodship T H, Donne R L, Pirson Y, Nicholls A, Ward R M, Turnpenny P, Goodship J A
Department of Medicine, University of Newcastle upon Tyne, England, United Kingdom.
Kidney Int. 1998 Apr;53(4):836-44. doi: 10.1111/j.1523-1755.1998.00824.x.
Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for factor H lies within the region. Subsequent mutation analysis of the factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of serum factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with factor H deficiency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.
成人溶血性尿毒症综合征（HUS）的发病率和死亡率很高，尽管有诸多理论，但病因仍不明。虽然家族性HUS罕见，但它为阐明可能与获得性HUS相关的潜在机制提供了独特机会。我们基于候选基因方法进行了一项基因连锁研究。由标记D1S212和D1S306界定的一个共同区域，位于1q32，距离为26厘摩，与该疾病共分离（Z最大值3.94）。我们证明补体因子H基因位于该区域内。随后对补体因子H基因的突变分析在HUS患者中发现了两个突变。在一名患有散发性/复发性疾病的个体中，我们发现了一个突变，包括一个缺失、随后的移码和过早的终止密码子，导致血清补体因子H水平为正常的一半。在三个家族中的一个家族中，外显子20存在一个点突变，导致精氨酸变为甘氨酸，这可能会改变补体因子H蛋白的结构，进而改变其功能。补体因子H是一种主要的血浆蛋白，在补体激活的替代途径中起关键调节作用。鉴于这些发现以及先前关于补体因子H缺乏患者发生HUS的报道，我们推测补体因子H异常可能参与了HUS的病因。
