Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.
Mol Immunol 2007 Jan
PMID:Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. 1688 52

A total of 1,000 school boys ages 14-18 years, were randomly selected from six schools of Kermanshah and screened for G6PD deficiency. Fifty-three out of 1,000 were found to be severely G6PD deficient giving a frequency of 5.3% for G6PD deficiency in males in Kermanshah. We performed DNA analysis on 68 G6PD deficient children, 52 school boys and 16 children with the history of favism and hemolytic anemia using a combination of PCR-RFLP technique, single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Three polymorphic G6PD mutations were identified: G6PD Mediterranean, Chatham and Cosenza. The commonest allele was found to be the G6PD Mediterranean (91.2%) followed by the G6PD Chatham (7.3%) and the G6PD Cosenza (1.5%). Haplotype analysis revealed that 56 out of 62 (90%) G6PD Mediterranean was linked to haplotype BclI(+) (1311T). In contrast, all G6PD Chatham and Cosenza had haplotype BclI(-) (1311C). The polymorphism IVS11-93 (T-->C) was present in 88.5% of the subjects studied. Only 4/55 (7.3%) of the Mediterranean alleles were associated with the T form and were always related to the nt 1311C. Our findings indicate that the allele frequency of G6PD Mediterranean mutation in Kermanshah is higher than those from two Fars ethnic groups living in Northern and Southern Iran. Nevertheless, they are in strict accordance with a previous report of the prevalence of the G6PD Mediterranean in Kurdish and Middle East population. Also, of strong association of the G6PD Mediterranean mutation and the presence of the polymorphism nt 1311C-->T in the Kermanshah population demonstrate that the presence of this mutation may be the result of migrations that have taken place through the history of Iran.
Blood Cells Mol Dis
PMID:Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in the Kurdish population of Western Iran. 1693 74

Several mutations in the CFH gene have been described in non-Shiga-toxin-associated haemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by haemolytic anaemia, thrombocytopenia and acute renal failure. Mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (CD46) and complement factor I (CFI), were also involved in the pathogenesis of the disease. Anyway, mutations in the three genes account for no more than 50% of cases of non-Stx-HUS. Human complement factor H related 5 (CFHR5) is a recently characterised member of the human complement factor H (CFH) family that has been found as a component of immune deposits in human kidney with sclerotic lesions from different causes. CFHR5 possesses cofactor activity and has been proposed to play a role in complement regulation in the glomerulus. We screened CFHR5 gene for variations potentially involved in the aetiology of HUS. Forty-five patients with HUS and 80 controls were analysed. Altogether, 5 genetic variants in CFHR5 were found in overall 9/45 HUS patients and in 4/80 controls. Statistical analysis showed that allelic variants in CFHR5 were prefentially associated with HUS. Based on these data, we conclude that, though not causative, CFHR5 genetic alterations may play a secondary role in the pathogenesis of HUS.
Mol Immunol 2007 Mar
PMID:Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. 1700

Factor I (FI) is the major complement inhibitor that degrades C3b and C4b in the presence of cofactors such as factor H (FH) and membrane cofactor protein (MCP). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study, we report three unrelated patients with an identical heterozygous mutation, G261D, in the FI heavy chain who developed severe aHUS at different time points in their lives. Two of the patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or C3b. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded C3b and C4b in a manner comparable to wild-type protein. In conclusion, despite the association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation.
Mol Immunol 2007 Mar
PMID:A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. 1708 97

AcB55, AcB61 and CBA/N-Pk(slc) mice carry loss of function mutations in the erythrocyte specific pyruvate kinase gene (Pklr). In AcB55 and AcB61 (Pklr(I90N)) PK deficiency is protective against blood-stage malaria. The mechanistic basis of protection against malaria is unknown and was studied in these two mutant alleles in vivo. The Pklr(G338D) mutation of the CBA/N-Pk(slc) mutant is shown to be more deleterious than the Pklr(I90N) allele with respect to enzymatic activity and severity of hemolytic anemia, with a more dramatic reduction in the half-life of erythrocytes (increased turnover) in the CBA/N-Pk(slc) mice. The CBA/N-Pk(slc) mice are also shown to be highly resistant to infection with Plasmodium chabaudi AS when compared to CBA/J and CBA/N controls. Resistance to malaria, measured as lower levels of blood-stage replication of P. chabaudi, rapid elimination of infected erythrocytes and increased survival to infection, was greater in the Pklr(G338D) mutant, CBA/N-Pk(slc), than in the Pklr(I90N) mutant strains, AcB55/AcB61. These results strongly suggest a correlation between severity of PK-deficiency and extent of protection against malaria. Additionally, the protective effect is independent of the genetic background on which the Pklr mutations occurred.
Blood Cells Mol Dis
PMID:Pyruvate kinase deficiency: correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants. 1746 43

A common cause of hereditary nonspherocytic hemolytic anemia is pyruvate kinase deficiency, which is associated with lifelong chronic hemolysis. Pyruvate kinase deficiency has a worldwide distribution with a higher prevalence in the Caucasian population, and especially in Europe and North America. It is inherited in an autosomal fashion and over 180 different mutations have been described. Investigation of hemolytic anemia in Northern Ireland has uncovered 4 new cases of pyruvate kinase deficiency. Molecular investigation revealed a total of six different mutations. One mutation (p.Arg495Val) is reported here for the first time in a homozygous patient. Another mutant PKLR allele harbored a nonsense and frameshift mutation in cis: c.[721G>T; 826delG]. Considering the three previously described Irish cases of pyruvate kinase deficiency, this study raises the total number of pyruvate kinase-deficient Irish patients to seven in which a total of nine mutant PKLR alleles were identified. This indicates the absence of a founder pyruvate kinase mutation in the Northern Ireland population. Although pyruvate kinase deficiency is prevalent in the Caucasian population it is not reflected in the number of individuals diagnosed in Northern Ireland. Hence, many cases of pyruvate kinase deficiency may remain undetected possibly due to the resultant anemia being mild.
Blood Cells Mol Dis
PMID:Pyruvate kinase deficient hemolytic anemia in the Northern Irish population. 1757 81

The beta-thalassemia is associated with abnormality in beta-globin gene, leading to imbalanced synthesis of alpha-/beta-globin chains. Consequently, the excessive free alpha-globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at alpha-globin reduction and beta-globin enrichment on beta(654) (Hbb(th-4)/Hbb(+)) mouse, carrying a human splicing-deficient beta-globin allele (Hbb(th-4)). Lentiviral vectors of short hairpin RNA (shRNA) targeting alpha-globin and/or antisense RNA facilitating beta-globin correct splicing were microinjected into beta(654) single-cell embryos. Three transgenic strains were generated, as alpha(i)-Hbb(th-4)/Hbb(+)(shRNA), beta(a)-Hbb(th-4)/Hbb(+)(antisense) and alpha(i)beta(a)-Hbb(th-4)/Hbb(+)(both shRNA and antisense). Without notable abnormalities, all the founders and their offsprings showed sustained amelioration of hematologic parameters, ineffective erythropoiesis and extramedullary hematopoiesis. Augmented effects appeared in alpha(i)beta(a)-Hbb(th-4)/Hbb(+), which correlated with a better-balanced alpha-/beta-globin mRNA level. Among the transgenic mice integrated with shRNA and antisense RNA, one homozygous mouse (Hbb(th-4)/Hbb(th-4)) had been viable, and the 3-week survival rate for heterozygotes (Hbb(th-4)/Hbb(+)) was 97%, compared with 45.4% for untreated. Our data have demonstrated the feasibility of techniques for beta-thalassemia therapy by balancing the synthesis of alpha-/beta-globin chains.
Hum Mol Genet 2007 Nov 01
PMID:Restoration of the balanced alpha/beta-globin gene expression in beta654-thalassemia mice using combined RNAi and antisense RNA approach. 1771 93

Stomatin is a major integral membrane protein of human erythrocytes, the absence of which is associated with a form of hemolytic anemia known as hereditary stomatocytosis. However, the function of stomatin is not fully understood. An open reading frame, PH1511, from the hyperthermophilic archaeon Pyrococcus horikoshii encodes p-stomatin, a prokaryotic stomatin. Here, we report the first crystal structure of a stomatin ortholog, the core domain of the p-stomatin PH1511p (residues 56-234 of PH1511p, designated as PhSto(CD)). PhSto(CD) forms a novel homotrimeric structure. Three alpha/beta domains form a triangle of about 50 A on each side, and three alpha-helical segments of about 60 A in length extend from the apexes of the triangle. The alpha/beta domain of PhSto(CD) is partly similar in structure to the band-7 domain of mouse flotillin-2. While the alpha/beta domain is relatively rigid, the alpha-helical segment shows conformational flexibility, adapting to the neighboring environment. One alpha-helical segment forms an anti-parallel coiled coil with another alpha-helical segment from a symmetry-related molecule. The alpha-helical segment shows a heptad repeat pattern, and mainly hydrophobic residues form a coiled-coil interface. According to chemical cross-linking experiments, PhSto(CD) would be able to assemble into an oligomeric form. The coiled-coil fold observed in the crystal probably contributes to self-association.
J Mol Biol 2008 Feb 22
PMID:Crystal structure of a core domain of stomatin from Pyrococcus horikoshii Illustrates a novel trimeric and coiled-coil fold. 1818 67

Several mouse models of sickle cell disease have been developed for the study of the pathophysiology of sickle cell disease and the investigation of drug and gene therapies. In previous years, we produced a sickle cell anemia mouse model in which the endogenous mouse alpha- and beta-globin genes were knocked out and replaced by the human alpha- and beta(s)-globin transgenes. The beta(s)-globin gene was contained in a 240 kb YAC that preserved the entire native genomic context of the beta-globin locus. These mice have hemolytic anemia, reticulocytosis and irreversible sickle cells in the peripheral blood, as well as other pathological features of sickle cell disease. However, in the embryo, the gamma-globin, like the mouse embryonic globin, declined quickly, and was replaced by beta(s)-globin expression from 12 days of gestation. The low level of fetal hemoglobin expression in utero led to intrauterine sickling and fetal death so that very few live-born sickle cell anemia mice could be obtained. To rescue these mice from intrauterine death, we investigated the effect of placing the pregnant mothers in a high O(2) environment. From the tenth day of gestation onwards, we placed the mothers into a chamber containing 50% O(2) and kept them with the newborn pups in it for another 10 days after birth. The frequency of sickle cell anemia mice we obtained was increased from less than 2% to 35%. The survived sickle cell anemia mice develop congestion, atrophy, and infarcts in multiple organs similar to those found in patients with sickle cell disease. We conclude that a high oxygen environment can be used to obtain more sickle cell anemia mice in those models that have a high perinatal mortality. The higher yield of these mice has facilitated physiological and therapeutic studies of sickle cell anemia.
Blood Cells Mol Dis
PMID:High oxygen environment during pregnancy rescues sickle cell anemia mice from prenatal death. 1820 38

Hereditary pyrimidine 5'-nucleotidase deficiency is the most frequent enzymopathy of red blood cell nucleotide metabolism that causes hereditary non-spherocytic hemolytic anemia. The disease is usually characterized by mild-to-moderate hemolytic anemia, reticulocytosis and hyperbilirubinemia. To date, diagnosis ultimately depends upon demonstration of a reduced level of pyrimidine 5'-nucleotidase type-I (P5'N-1) activity in red cells and detection of mutations in the P5'N-1 gene. To unravel the causes of the P5'N deficiency and to obtain data for a definitive diagnosis three newly described missense mutations (c.187T>C, c.469G>C and c.740T>C) identified in patients with hemolytic anemia have been characterized at protein level. The mutant enzymes (C63R, G157R and I247T) were obtained as recombinant forms and purified to homogeneity. The enzymes were altered, although to a different extent, in both thermal stability and catalytic efficiency. The catalytic efficiency of all mutants was reduced especially towards UMP (up to more than 200 times), owing to the increased Km values (approximately, 10-25 times higher). The G157R enzyme was severely heat unstable and lost half of its activity after about 23 min of incubation at 37 degrees C. At higher temperature C63R and I247T mutants as well were less stable than the wild-type enzyme. Therefore, although the mutations targeted different regions of the P5'N-1 structure, they produced similar effects on the molecular properties of the enzyme. Thus, all affected amino acids are functionally and structurally important for preserving the enzyme activity during the red cell life span.
Blood Cells Mol Dis
PMID:Molecular basis of pyrimidine 5'-nucleotidase deficiency caused by 3 newly identified missense mutations (c.187T>C, c.469G>C and c.740T>C) and a tabulation of known mutations. 1849 1


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