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Are HUS and TTP genetically determined?
Kidney International, Vol. 53 (1998), pp. 1085–1086
EDITORIAL
Are HUS and TTP genetically determined? Hemolytic uremic syndrome (HUS), and the related condition thrombotic thrombocytopenic purpura (TTP), are diseases of non-immune hemolytic anemia, thrombocytopenia and renal failure with platelet thrombi in the microcirculation of various organs [1]. The characteristic lesion, thrombotic microangiopathy (TMA), is unique to these syndromes and consists of vessel wall thickening, with swelling and detachment of endothelial cells from the basement membrane and with accumulation of fluffy material in the subendothelium [1]. The typical form of HUS of children manifests with bloody diarrhea mostly associated to Escherichia coli infection and lesions are related to a toxin, Shiga-like toxin or verocytotoxin, unique of certain strain of E. coli. There are hereditary forms of HUS mostly with a recessive trait, with dominant inheritance occasionally reported [2]. In affected families members may have HUS as the sole manifestation of the disease, in other instances clinical manifestation may rather be reminiscent of TTP. Occasionally clinical manifestation of both HUS and TTP can co-exist in the same patient [2]. A recent report [3] of increased incidence of HLA B40 group antigens in children with HUS was taken to suggest that HLA B40 is linked to susceptibility genes, as to cause disease manifestation upon concomitant exposure to triggering factors. HUS recurrence in renal allografts as well as improvement following plasma exchange, at least in some patients with familial HUS, would suggest a genetic abnormality in plasma proteins, that, together with findings of reduced levels of C3 consistently reported since 1974 in sporadic and familial variants of the disease, have suggested an inherited defect of C3 synthesis. A major step forward in defining and understanding underlying genetic defect of familial HUS was made by three distinct reports published from 1981 to 1994 [4 – 6], showing a genetic deficiency of factor H—a regulatory protein of the alternative complement pathway—in HUS, leading to low levels of complement protein C3. In the more recent of the above studies [6] HUS was reported in two siblings: one died at an early age from diarrhea-associated HUS, while the other had three episodes of HUS since the age of 19 years. This latter patient and her sister, who was asymptomatic at that time, were both found to have very low factor H (5% of normal). Several members of the family had 50% levels, suggesting an autosomal recessive defect. In this issue of Kidney International, Warwicker et al [7] demonstrated in three large families with HUS, that an area on chromosome 1q, that contains the gene for factor H, segregates with the disease, which further supports that low C3 in the setting of familial HUS depends on an inherited
Key words: hemolytic anemia, thrombotic microangiopathy, diarrhea, E. coli infection, hereditary HUS, complement, factor H. Received for publication November 24, 1997 Accepted for publication November 25, 1997
© 1998 by the International Society of Nephrology
factor H deficiency. At variance with the family described earlier by Pichette and coworkers [6], factor H levels were not reduced in any members of the three families. The authors state that normal levels of factor H do not exclude an underlying functional abnormality. Actually, in affected members and obligate carriers within one family they found a point mutation in short consensus repeat (SCR) 20 —factor H protein is composed of 20 homologous SCR domains— causing an arginine to glycine change. Factor H molecule, in addition to the two C3b binding sites originally described which are located on 1– 4 and 6 –10 domains, has been recently found to have a third C3b binding site that resides in the 16 –20 region. It is therefore theoretically possible that the point mutation described by Warwicker et al [7] in exon 20 might alter the structure and hence the function of factor H; however, functional and mutagenesis studies are mandatory to clarify its real significance in the context of disease pathophysiology. In the other two families, no mutations were detected in the coding region of factor H gene, although mutations in the promoter or within introns cannot be excluded. Given the fact that linkage analysis has been performed on a huge candidate region, which includes other genes encoding for complement regulatory proteins (DAF, CR1 and factor H-related proteins) [8], it is more plausible that other genes, possibly including some of the above, are actually involved in causing hereditary HUS. Warwicker et al [7] also described a mutation of factor H gene in an individual with relapsing HUS but with no familial history of HUS. The mutation comprises a deletion causing a premature termination codon that results in 50% reduced levels of factor H. These data raise the intriguing possibility of negative family history being still compatible with a genetically determined HUS, and even that de novo mutations in factor H and other related genes might predispose to the disease. In their paper the authors refer to unpublished results from their laboratory describing a polymorphism in an NF-kB responsive element in the promoter region of factor H and speculate that polymorphic variants might confer a genetic predisposition to post-infectious HUS. The speculation is based on the fact that in the siblings who suffered HUS already reported by Pichette, one had recurrent HUS and factor H deficiency and the other presented with typical diarrhea-associated HUS (factor H was not measured in the latter, however). While the possibility that polymorphisms in the promoter and in the coding region of factor H might have a role in familial and recurrent HUS appears very fascinating, one may also ask the question of whether congenital defects of the complement system may have a role in driving predisposition to HUS following E. coli infections. Can factor H be regarded now as the candidate gene involved in familiar predisposition to HUS? It is possible. Certainly investigating C3 and factor H levels in individuals with familial and recurrent history of HUS is something that needs to be done in the future. The heterogeneity of the manifestations of HUS (typical, recurrent, familial with autosomal dominant inheritance,
1085
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Noris and Remuzzi: Editorial
and familial with autosomal recessive inheritance), clearly indicates that much work is yet to be done and it is likely that more than one gene is involved. We recently looked for possible complement alterations in patients with familial forms of TTP, and found a high incidence of low C3 levels exactly as observed with HUS [9]. Of interest, in two families who had one member affected with HUS and one with TTP, low C3 levels were found both in patients and in some of their relatives. Altogether these preliminary results support the concept that HUS and TTP are different manifestations of the same inherited defect. Perhaps genetics will contribute to resolve the old issue of whether HUS and TTP are the same or different diseases [10].
3. 4. 5. 6. 7.
MARINA NORIS and GIUSEPPI REMUZZI Bergamo, Italy
8.
Reprint requests to Giuseppe Remuzzi, M.D., “Mario Negri” Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. E-mail: [email protected]
9.
REFERENCES 1. REMUZZI G, RUGGENENTI P: The hemolytic uremic syndrome. (Perspectives in Clinical Nephrology) Kidney Int 47:2–19, 1995 2. KAPLAN BS, KAPLAN P: Hemolytic uremic syndrome in families, in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Pur-
10.
pura, edited by KAPLAN BS, TROMPETER R, MOAKE J, New York, Marcel Dekker, Inc. 1992, pp 213–225. SHETH KJ, GILL JC, LEICHTER HE, HAVENS PL, HUNTER JB: Increased incidence of HLA-B40 group antigens in children with hemolytic-uremic syndrome. Nephron 68:433– 436, 1994 THOMPSON RA, WINTERBORN MH: Hypocomplementaemia due to a genetic deficiency of B1H globulin. Clin Exp Immunol 46:110 –119, 1981 ROODHOOFT AM, MCLEAN RH, ELST E, VAN ACKER KJ: Recurrent hemolytic uremic syndrome and acquired hypomorphic variant of the third component of complement. Pediatr Nephrol 4:597–599, 1990 PICHETTE V, QUERIN S, SCHURCH W, BRUN G, LEHNER-NETSCH G, DELAGE J-M: Familial haemolytic-uraemic syndrome and homozygous factor H deficiency. Am J Kidney Dis 24:936 –941, 1994 WARWICKER P, GOODSHIP THJ, DONNE RL, PIRSON Y, NICHOLLS A, WARD RM, TURNPENNY P, GOODSHIP JA: Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53: 836 – 844, 1998 REY-CAMPOS J, RUBINSTEIN P, DE CORDOBA SR: A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP. J Exp Med 167:664 – 669, 1988 VASILE B, RUGGENENTI P, FASSI A, GAMBA S, CRIPPA A, ROBBA L, REMUZZI G: Familial thrombotic microangiopathy (TMA): Low C3 complement component and anticardiolipin antibodies (ACA) clustering in a case-control study of 9 families. (abstract) J Am Soc Nephrol 8:396, 1997 REMUZZI G: HUS and TTP: Variable expression of a single entity. Kidney Int 32:292–308, 1987.
EDITORIAL
Are HUS and TTP genetically determined? Hemolytic uremic syndrome (HUS), and the related condition thrombotic thrombocytopenic purpura (TTP), are diseases of non-immune hemolytic anemia, thrombocytopenia and renal failure with platelet thrombi in the microcirculation of various organs [1]. The characteristic lesion, thrombotic microangiopathy (TMA), is unique to these syndromes and consists of vessel wall thickening, with swelling and detachment of endothelial cells from the basement membrane and with accumulation of fluffy material in the subendothelium [1]. The typical form of HUS of children manifests with bloody diarrhea mostly associated to Escherichia coli infection and lesions are related to a toxin, Shiga-like toxin or verocytotoxin, unique of certain strain of E. coli. There are hereditary forms of HUS mostly with a recessive trait, with dominant inheritance occasionally reported [2]. In affected families members may have HUS as the sole manifestation of the disease, in other instances clinical manifestation may rather be reminiscent of TTP. Occasionally clinical manifestation of both HUS and TTP can co-exist in the same patient [2]. A recent report [3] of increased incidence of HLA B40 group antigens in children with HUS was taken to suggest that HLA B40 is linked to susceptibility genes, as to cause disease manifestation upon concomitant exposure to triggering factors. HUS recurrence in renal allografts as well as improvement following plasma exchange, at least in some patients with familial HUS, would suggest a genetic abnormality in plasma proteins, that, together with findings of reduced levels of C3 consistently reported since 1974 in sporadic and familial variants of the disease, have suggested an inherited defect of C3 synthesis. A major step forward in defining and understanding underlying genetic defect of familial HUS was made by three distinct reports published from 1981 to 1994 [4 – 6], showing a genetic deficiency of factor H—a regulatory protein of the alternative complement pathway—in HUS, leading to low levels of complement protein C3. In the more recent of the above studies [6] HUS was reported in two siblings: one died at an early age from diarrhea-associated HUS, while the other had three episodes of HUS since the age of 19 years. This latter patient and her sister, who was asymptomatic at that time, were both found to have very low factor H (5% of normal). Several members of the family had 50% levels, suggesting an autosomal recessive defect. In this issue of Kidney International, Warwicker et al [7] demonstrated in three large families with HUS, that an area on chromosome 1q, that contains the gene for factor H, segregates with the disease, which further supports that low C3 in the setting of familial HUS depends on an inherited
Key words: hemolytic anemia, thrombotic microangiopathy, diarrhea, E. coli infection, hereditary HUS, complement, factor H. Received for publication November 24, 1997 Accepted for publication November 25, 1997
© 1998 by the International Society of Nephrology
factor H deficiency. At variance with the family described earlier by Pichette and coworkers [6], factor H levels were not reduced in any members of the three families. The authors state that normal levels of factor H do not exclude an underlying functional abnormality. Actually, in affected members and obligate carriers within one family they found a point mutation in short consensus repeat (SCR) 20 —factor H protein is composed of 20 homologous SCR domains— causing an arginine to glycine change. Factor H molecule, in addition to the two C3b binding sites originally described which are located on 1– 4 and 6 –10 domains, has been recently found to have a third C3b binding site that resides in the 16 –20 region. It is therefore theoretically possible that the point mutation described by Warwicker et al [7] in exon 20 might alter the structure and hence the function of factor H; however, functional and mutagenesis studies are mandatory to clarify its real significance in the context of disease pathophysiology. In the other two families, no mutations were detected in the coding region of factor H gene, although mutations in the promoter or within introns cannot be excluded. Given the fact that linkage analysis has been performed on a huge candidate region, which includes other genes encoding for complement regulatory proteins (DAF, CR1 and factor H-related proteins) [8], it is more plausible that other genes, possibly including some of the above, are actually involved in causing hereditary HUS. Warwicker et al [7] also described a mutation of factor H gene in an individual with relapsing HUS but with no familial history of HUS. The mutation comprises a deletion causing a premature termination codon that results in 50% reduced levels of factor H. These data raise the intriguing possibility of negative family history being still compatible with a genetically determined HUS, and even that de novo mutations in factor H and other related genes might predispose to the disease. In their paper the authors refer to unpublished results from their laboratory describing a polymorphism in an NF-kB responsive element in the promoter region of factor H and speculate that polymorphic variants might confer a genetic predisposition to post-infectious HUS. The speculation is based on the fact that in the siblings who suffered HUS already reported by Pichette, one had recurrent HUS and factor H deficiency and the other presented with typical diarrhea-associated HUS (factor H was not measured in the latter, however). While the possibility that polymorphisms in the promoter and in the coding region of factor H might have a role in familial and recurrent HUS appears very fascinating, one may also ask the question of whether congenital defects of the complement system may have a role in driving predisposition to HUS following E. coli infections. Can factor H be regarded now as the candidate gene involved in familiar predisposition to HUS? It is possible. Certainly investigating C3 and factor H levels in individuals with familial and recurrent history of HUS is something that needs to be done in the future. The heterogeneity of the manifestations of HUS (typical, recurrent, familial with autosomal dominant inheritance,
1085
1086
Noris and Remuzzi: Editorial
and familial with autosomal recessive inheritance), clearly indicates that much work is yet to be done and it is likely that more than one gene is involved. We recently looked for possible complement alterations in patients with familial forms of TTP, and found a high incidence of low C3 levels exactly as observed with HUS [9]. Of interest, in two families who had one member affected with HUS and one with TTP, low C3 levels were found both in patients and in some of their relatives. Altogether these preliminary results support the concept that HUS and TTP are different manifestations of the same inherited defect. Perhaps genetics will contribute to resolve the old issue of whether HUS and TTP are the same or different diseases [10].
3. 4. 5. 6. 7.
MARINA NORIS and GIUSEPPI REMUZZI Bergamo, Italy
8.
Reprint requests to Giuseppe Remuzzi, M.D., “Mario Negri” Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. E-mail: [email protected]
9.
REFERENCES 1. REMUZZI G, RUGGENENTI P: The hemolytic uremic syndrome. (Perspectives in Clinical Nephrology) Kidney Int 47:2–19, 1995 2. KAPLAN BS, KAPLAN P: Hemolytic uremic syndrome in families, in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Pur-
10.
pura, edited by KAPLAN BS, TROMPETER R, MOAKE J, New York, Marcel Dekker, Inc. 1992, pp 213–225. SHETH KJ, GILL JC, LEICHTER HE, HAVENS PL, HUNTER JB: Increased incidence of HLA-B40 group antigens in children with hemolytic-uremic syndrome. Nephron 68:433– 436, 1994 THOMPSON RA, WINTERBORN MH: Hypocomplementaemia due to a genetic deficiency of B1H globulin. Clin Exp Immunol 46:110 –119, 1981 ROODHOOFT AM, MCLEAN RH, ELST E, VAN ACKER KJ: Recurrent hemolytic uremic syndrome and acquired hypomorphic variant of the third component of complement. Pediatr Nephrol 4:597–599, 1990 PICHETTE V, QUERIN S, SCHURCH W, BRUN G, LEHNER-NETSCH G, DELAGE J-M: Familial haemolytic-uraemic syndrome and homozygous factor H deficiency. Am J Kidney Dis 24:936 –941, 1994 WARWICKER P, GOODSHIP THJ, DONNE RL, PIRSON Y, NICHOLLS A, WARD RM, TURNPENNY P, GOODSHIP JA: Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53: 836 – 844, 1998 REY-CAMPOS J, RUBINSTEIN P, DE CORDOBA SR: A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP. J Exp Med 167:664 – 669, 1988 VASILE B, RUGGENENTI P, FASSI A, GAMBA S, CRIPPA A, ROBBA L, REMUZZI G: Familial thrombotic microangiopathy (TMA): Low C3 complement component and anticardiolipin antibodies (ACA) clustering in a case-control study of 9 families. (abstract) J Am Soc Nephrol 8:396, 1997 REMUZZI G: HUS and TTP: Variable expression of a single entity. Kidney Int 32:292–308, 1987.