Arbeitsgruppe Genetische Instabilitätssyndrome
Leitung: Prof. Dr. med. Detlev Schindler
Detlev Schindler received his M.D. degree from the University of Würzburg School of Medicine. He is board certified in Pediatrics, Medical and Human Genetics. Since 1997 he is a Professor in the Department of Human Genetics. He heads the Division of Somatic Cell and biochemical Genetics within the Department of Human Genetics
Central theme are the molecular, cell biological and clinical manifestations of human genetic instability syndromes as they relate to the premature occurrence of cancer and aging. The three principal syndromes include Fanconi anemia, Ataxia telangiecasia and Nijmegen breakage syndrome, with emphasis on Fanconi anemia (FA). FA patients show growth retardation, congenital defects, childhood bone marrow failure and a strongly increased risk for neoplasias, most frequently AML and squamous cell carcinomas. FA is a genetically heterogeneous disease caused by biallelic mutations in at least 12 different genes. The FA proteins play an essential role in maintaining the stability of the human genome. They interact among themselves and with a variety of other caretaker proteins, including the known breast cancer genes BRCA1 and BRCA2. The BRCA1-interacting protein BRIP1 was recently identified as the FA gene FANCJ, and the BRCA2-interacting protein PALB2 was shown to be identical with the FA gene FANCN. Biallelic mutations in FANCN cause early onset childhood cancers. Both FANCJ and FANCN have been identified as low penetrance breast cancer genes. Hematopoietic stem cell transplantation is the only curative treatment, but a number of patients develop revertant mosaicism in their blood lineage cells as a kind of “natural gene therapy”. The laboratory serves as a diagnostic center for the confirmation or exclusion of Fanconi anemia, for complementation analysis via retroviral complementation (in collaboration with Prof. Hanenberg, Düsseldorf), and for the pre- and postnatal mutation analysis. Current research efforts are directed at the discovery of additional FA genes, at deciphering the molecular causes of the cell cycle aberrations in FA cells, and at understanding the molecular mechanisms of somatic reversions (revertant mosaicism).
Other caretaker syndromes that are variably investigated by the group include Ataxia telangiectasia and other radiosensitivity syndromes including Nijmegen breakage syndrome and Ligase IV deficiency syndrome, Werner adult progeria syndrome, and microcephaly-syndromes caused by mutations in microcephalin IV.
Reid S, Schindler D, Hanenberg H, et al: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nature Genetics 2007; 39:162-4
Bogliolo M, Lyakhovich A, Callen E, et al: Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability. EMBO J 2007; 26:1340-51
Huck K, Hanenberg H, Gudowius S, et al: Delayed diagnosis and complications of Fanconi anemia at advanced age – a paradigm. Br J Haematol 206; 133: 188-97
Heinrich T, Prowald C, Friedl R, et al: Exclusion/confirmation of Ataxia telangiectasia via cell cycle testing. Eur J Pediat 2006; 165: 250-7
Levran O, Attwooll C, Henry RT, et al: The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nature Genetics 2005; 37:921-2