Analyse der variablen Expressivität beim Nijmegen Breakage Syndrom (NBS)

• Applicant: Professor Dr. Martin J. Digweed
• Subject Area: Human Genetics
• Term: from 2009 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 129836450

Over 90% of patients with Nijmegen Breakage Syndrome (NBS), a hereditary cancer disorder, are homoallelic for a 5bp deletion in the NBN gene. This hypomorphic mutation leads to a carboxyterminal protein fragment. Haploinsufficiency for NBN is associated with increased cancer risk for heterozygotes, and variation in the amount of the carboxyterminal protein correlates in homozygotes with cancer occurrence. Discovering the molecular basis for this variation is a major goal of the project and for this, patient cells and a humanized mouse model will be employed. Further examples of variable expressivity in NBS are found at the level of immunodeficiency and chromosomal instability, reflecting NBN’s role in DNA double strand break repair. Potential modifiers of NBN will be searched for by defining the proteins interacting directly with NBN or affected by its absence. These modifiers will then be evaluated in our patient panel for their contribution to phenotypic variability.

• DFG Programme: Research Grants