Funded by the Italian Association of Shwachman-Diamond Syndrome (A.I.S.S.)

  • “Mechanisms  underpinning the DNA-damage response in lymphoblastoid cell lines from Shwachman-Diamond patients”, coordinated by UniPv (2014) – Principal Investigator: Dr. J. Morini.

Many genetic diseases are known to be characterized by a strong impairment of the DNA damage repair machinery. These pathologies (e.g. Cockayne’s syndrome, Ataxia-Telangiectasia, etc.) are caused by mutations in different proteins directly involved in the DNA repair pathways. In such syndromes the loss of function of different pathways leads to a higher radiosensitivity.

Shwachman-Diamond syndrome (SDS), a rare genetic disease caused by mutation in the SBDS gene. SBDS protein is not directly involved in DNA repair pathways, but it is known that it co-immunoprecipitates with proteins directly involved in DNA repair.

Since SDS patients are susceptible of repeated radiological investigations and are exposed to the risk of undergoing bone marrow pre-transplant conditioning regimen, the aim of this project was to reach a deeper knowledge of the mechanisms involved in the altered stress response in cells lacking of SBDS gene regarding, in particular, the role of SBDS absence in DNA double strand break (DSB) repair impairment.

  • “Susceptibility to oxidative stress caused by ionizing radiation exposure in Shwachman-Diamond syndrome affected patients’ lymphocytes”, coordinated by UniPv (2013) – Principal Investigator: Dr. J. Morini.

Shwachman-Diamond syndrome (SDS, MIM#260400) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow failure, and a striking cumulative risk of progression to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) caused to mutation in the SBDS gene.

SBDS-deficiency sensitize cells to a variety of stress conditions (e.g. DNA damage) indicating that SBDS is required for cells to deal efficiently with adverse conditions. Moreover, SBDS-knockout led to increased ROS levels in some experimental set-up. Furthermore, elevated ROS levels are related to the accelerated Fas-mediated apoptosis which characterizes SBDS-deficient cells.

The aim of this research project was to investigate the effects of the exposure of lymphocytes derived from SDS patients to ionizing radiation and subsequently to study the effects of direct damage and indirect damage (oxidative stress) caused by radiation itself.

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