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Rare Diseases

Laboratory of Immunology and Genetic of Rare Diseases

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Senior Advisor
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The Laboratory focuses on the identification of the genetic and biochemical factors responsible or predisposing to the onset and to the progression of rare diseases such as Hemolytic Uremic Syndrome (HUS), Thrombotic Thrombocytopenic Purpura (TTP), immune-complex membranoproliferative glomerulonephritis (IC-MPGN), C3 glomerulopathy (C3G), fibronectin glomerulopathy and Steroid-Resistant Nephrotic Syndrome (SRNS).

The aims of the laboratory are to improve the diagnostic criteria of these rare diseases and to deepen the understanding of the altered molecular mechanisms in order to identify new targeted therapies for patients.

From 2010 the laboratory carries out genetic and biochemical investigations in agreement with the National Health Service. These investigations are conducted on the following rare diseases:

  • HUS (atypical hemolytic uremic syndrome)
  • TTP ( thrombotic thrombocytopenic purpura)
  • MPGN (immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy)
  • SRNS (Steroid-Resistant Nephrotic Syndrome)
  • Alport syndrome
  • Fabry disease
  • Polycystic kidney disease

The laboratory faced the health emergency from the SARS-CoV-2 outbreak by becoming in 2021 one of the reference laboratories for SARS-CoV-2 sequencing in Lombardy.

Since May 2021 the laboratory has dealt with the genetic surveillance of the SARS-CoV-2 variants through the sequencing of RNA sample from molecular swab and has participated to the monthly surveys promoted by the Italian Health Institute. This activity, essential to understand the spread of the virus in the province of Bergamo and to prevent the spread of dangerous variants, is carried out in collaboration with the ASST-Bergamo Est).

In September 2020 the laboratory launched the ORIGIN project, with the aim to investigate whether a relationship between COVID-19 and genetic factors exists. The idea behind the ORIGIN project is that the genetic variations in the DNA from an individual can influence the severity of COVID-19 and may explain the different responses to infection.


Identification of new disease-associated genes

Results of research studies done during the last 15 years allowed the identification of several genes which alterations are responsible of rare diseases such as the atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), Immune Complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and steroid resistant nephrotic syndrome (SRNS). However these abnormalities explain the disease only for a portion of patients. Thus the objective of our project is to identify other genes involved in the pathogenesis of the above rare diseases in those patients without mutations in the known disease-associated genes. To this purpose, we analyze the DNA of patients and their relatives by innovative techniques, including the sequencing of the whole exome by “Next generations sequencing”, and the search for deletions, duplications and genomic rearrangements by “Single molecule real time sequencing” and “Multiplex ligation-dependent probe amplification”. The knowledge of the genetic factors involved in the development of aHUS, C3G, IC-MPGN and SRNS will contribute to achieve a precise and early diagnosis, to understand the causes of the diseases and to identify specific therapies.

Development of diagnostic panels for the sequencing of new genes involved in rare diseases, up to the evaluation of the entire exome

The genetic diagnosis of several rare diseases is rather complex: these diseases are characterized by a high genetic heterogeneity –i.e. in different patients the same disease may be caused by mutations in different genes-. Traditional sequencing methods, such as Sanger sequencing, are not suitable for genetic diagnosis, since they require long analytical time and are expensive. In our laboratory we have developed diagnostic panels that are specific for the genes associated with some rare diseases such as the atypical hemolytic syndrome (aHUS), C3 glomerulopathy (C3G), Immune Complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and steroid resistant nephrotic syndrome (SRNS). These panels coupled with the next generation sequencing platform allow the analysis of several genes together in shorter time and with reduced costs than Sanger sequencing. We designed this project with the goal to ameliorate the diagnostic resources of rare disease and to improve at the same time our knowledge of the genetic causes of these diseases through the inclusion in the panels of new candidate genes.

Characterization of the functional consequences of the identified genetic alterations

The evaluation of the functional consequences of gene mutations associated with rare diseases and the investigation of how these abnormalities influence the synthesis and/or the function of the encoded proteins, have a crucial impact in the comprehension of the molecular mechanisms responsible for the onset of a given disease. The effects of gene mutations may be very diverse depending on the type of the mutation and on its localization in the protein. Indeed, at cellular level, different mutations may have different impact on the synthesis, the cellular transport, the localization and the function of the mutant protein. To study the functional consequences of the mutations in known disease-associated genes as well as in new genes that we identified in our patients with aHUS, C3G, IC-MPGN or SRNS, we generate the recombinant mutant and wild-type proteins and we induce their expression in mammalian and insect stable cell lines. Thereafter, we evaluate the effects of the mutations on protein synthesis and secretion and on protein function by specific biochemical and molecular tests.

Evaluation of the pathogenic role of autoantibodies associated with rare diseases such as HUS, IC-MPGN and C3G

During the last 10 years several types of autoantibodies have been identified that are responsible of the activation of the alternative pathway of complement, resulting in tissue and organ injury in patients with aHUS, IC-MPGN and C3G. In aHUS the most common antibodies target a complement regulatory protein called factor H, whereas about half of patients with IC-MPGN or C3G carry an heterogeneous group of antibodies collectively called C3NeFs. C3NeFs stabilize the C3 convertase, a protease complex that is crucial for the activation of the alternative pathway of complement. Through the purification of the antibodies from the serum of patients with either aHUS or IC-MPGN/C3G and after setting up specific functional tests, we could document that antibodies isolated from different patients have different molecular targets and different functional effects in the complement cascade. More importantly we found that the abnormalities associated with the specific autoantibodies correlate with clinical parameters. Further studies are ongoing in our laboratory to characterize the specific autoantibodies and to identify the causes underlying their formation in the circulation of patients. Several drugs are under clinical development, which inhibit the complement cascade at various levels. The results of our studies will hopefully help designing personalized therapies, targeted to counteract the effect of the specific autoantibodies identified in each patient.

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