Genetic studies into inherited and sporadic hemolytic uremic syndrome

被引:356
作者
Warwicker, P
Goodship, THJ
Donne, RL
Pirson, Y
Nicholls, A
Ward, RM
Turnpenny, P
Goodship, JA
机构
[1] Univ Newcastle Upon Tyne, Dept Med, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England
[2] Univ Newcastle Upon Tyne, Dept Human Genet, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England
[3] Univ Catholique Louvain, Renal Unit, Clin Univ St Luc, B-1200 Brussels, Belgium
[4] Royal Devon & Exeter Hosp, Renal Unit, Exeter EX2 5DW, Devon, England
[5] Royal Devon & Exeter Hosp, Clin Genet Serv, Exeter EX2 5DW, Devon, England
[6] Royal Victoria Infirm Trust, Dept Immunol, Newcastle Upon Tyne, Tyne & Wear, England
关键词
hemolytic uremic syndrome; complement factor H; inherited renal disease; genetic linkage; human chromosome 1;
D O I
10.1046/j.1523-1755.1998.00824.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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 mw 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 II lies within the region. Subsequent mutation analysis of the factor II 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.
引用
收藏
页码:836 / 844
页数:9
相关论文
共 33 条
[1]   Human factor H deficiency - Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism [J].
Ault, BH ;
Schmidt, BZ ;
Fowler, NL ;
Kashtan, CE ;
Ahmed, AE ;
Vogt, BA ;
Colten, HR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (40) :25168-25175
[2]   URINARY-EXCRETION OF PLATELET-ACTIVATING-FACTOR IN HEMOLYTIC UREMIC SYNDROME [J].
BENIGNI, A ;
BOCCARDO, P ;
NORIS, M ;
REMUZZI, G ;
SIEGLER, RL .
LANCET, 1992, 339 (8797) :835-836
[3]   ROLE OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 IN THE PATHOGENESIS AND OUTCOME OF THE HEMOLYTIC UREMIC SYNDROME [J].
BERGSTEIN, JM ;
RILEY, M ;
BANG, NU .
NEW ENGLAND JOURNAL OF MEDICINE, 1992, 327 (11) :755-759
[4]   INHERITED HEMOLYTIC UREMIC SYNDROME IN ADULTS [J].
BERNS, JS ;
KAPLAN, BS ;
MACKOW, RC ;
HEFTER, LG .
AMERICAN JOURNAL OF KIDNEY DISEASES, 1992, 19 (04) :331-334
[5]  
CAMERON JS, 1973, LANCET, V2, P975
[6]   FAMILIAL HEMOLYTIC UREMIC SYNDROME [J].
EDELSTEN, AD ;
TUCK, S .
ARCHIVES OF DISEASE IN CHILDHOOD, 1978, 53 (03) :255-256
[7]  
FARR MJ, 1975, Q J MED, V44, P161
[8]  
GASSER C, 1955, Schweiz Med Wochenschr, V85, P905
[9]  
JANSEN JH, 1994, CLIN EXP IMMUNOL S2, V97, P29
[10]  
Kaplan B. S., 1992, HEMOLYTIC UREMIC SYN