Rare Diseases: don't stop the research

Project location: ITALY
Project start date: January 2001 - Project end date: January 2002
Project number: 2001-15
Beneficiary: ARMR

Fellowship for a research on genes implicated in HUS/TTP


On November 20, 2000 the Nando Peretti Foundation granted a fellowship for a research on the genes implicated in the pathogenesis of familial and recurrent Haemolytic-Uraemic Syndrome, Thrombotic Thrombocytopenic Purpura (HUS/TTP) to the ARMR (Associazione per la Ricerca sulle Malattie Rare - Association for the Research on Rare Diseases), an Italian non-profit organization which promotes the research on the causes of rare diseases. The fellowship was awarded to Dr. Jessica Caprioli, who completed her study on the mutations of factor H gene in families with autosomal dominant or recessive HUS/TTP. The research was carried out at the Center of Researches "Aldo e Cele Daccò" in Ranica (Bergamo, Italy).



Research of genes implicated in the pathogenesis of familial and recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura.

The causes of Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura are now beginning to be understood, thanks to our and other lab's work. In particular we focused our efforts in analyzing two genes: factor H and ADAMTS13.

1) Studies on factor H gene and function
Factor H functions as a regulatory protein in a physiologic pathway (called complement) that is activated by infections and inflammatory processes. When complement is activated, it determines the lysis and death of bacteria and of inflammatory cells within the organism. Factor H intervenes inhibiting complement activation, in order to avoid that other cells of the body (in particular endothelial cells, that form a cell monolayer lining blood vessels) could be affected by complement hyper-activation.

  • We identified till now in the factor H gene 8 mutations, that are alterations of DNA sequence, in affected subjects from 5 families and in 3 patients with the recurrent form of the disease and no familial history.
  • We recently obtained the first evidences that demonstrate that the mutated factor H loses the capacity of protecting the endothelial cells of the body from being lysed by complement, thus favoring the occurrence of endothelial damage.
  • Epidemiological studies revealed that renal transplantation is not the treatment of choice for HUS patients with a mutation in factor H: in fact the disease always recurs in the transplanted kidney. For this reason we are now involved in performing factor H genetic analysis in patients with HUS that are waiting for a renal transplantation. This screening and genetic counseling is extremely important because it allows to identify patients in which renal transplantation has to be discouraged.

2) Studies on ADAMTS13 gene and function
ADAMTS13 is a protein that functions by cleaving and activating another protein called von Willebrand Factor (vWF); vWF is a protein that plays a major role in hemostasis. Upon injury, endothelial cells release vWF, that mediates the adhesion of platelets to the sites of lesion. Normally vWF is secreted as a large multimeric chain of vWF units, immediately cleaved by ADAMTS13 in smaller multimers.

  • Studies from our and other laboratories demonstrated that a marked reduction in ADAMTS13 activity is present in a number of HUS/TTP patients both during the acute phase of the diseases and at remission.
  • Studies on families demonstrated that the defect is inherited in a recessive way (this means that a partial defect is present in both parents, but is not enough to cause the disease. Only subjects that have a complete defect, coming half from the mother and half from the father, develop the disease).
  • We recently demonstrated that it is not possible to discriminate HUS and TTP on the basis of ADAMTS13 deficiency as the defect is common to both HUS and TTP.
  • We are at the moment analyzing the gene encoding for ADAMTS13 in order to identify the mutations leading to an impaired functionality of the protein.

General conclusions During the past year interesting results have been obtained in the comprehension of the pathogenesis of HUS/TTP; this will allow in the next future to study new therapeutic approaches that may be more specific and effective.

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