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Human Molecular Genetics, 1999, Vol. 8, No. 9 1769-1777
© 1999 Oxford University Press

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome

Martha Kalff-Suske, Anja Wild, Juliane Topp, Martina Wessling, Eva-Maria Jacobsen, Dorothea Bornholdt, Hartmut Engel, Heike Heuer, Cora M. Aalfs1, Margreet G. E. M. Ausems2, Rita Barone3, Andreas Herzog4, Peter Heutink5, Tessa Homfray6, Gabriele Gillessen-Kaesbach7, Rainer König8, Jürgen Kunze9, Peter Meinecke10, Dietmar Müller11, Renata Rizzo3, Sibylle Strenge12, Andrea Superti-Furga13 and Karl-Heinz Grzeschik+

Medizinisches Zentrum für Humangenetik, Philipps-Universität Marburg, D-35037 Marburg, Germany, 1Afdeling Klinische Genetica, Academisch Medisch Centrum, Universiteit van Amsterdam, NL-1105 AZ Amsterdam, The Netherlands, 2Klinisch Genetisch Centrum Utrecht, NL-3501 CA Utrecht, The Netherlands, 3Clinica Pediatrica, Universita di Catania, I-95125, Catania, Italy, 4D-06526 Sangerhausen, Germany, 5Klinische Genetica, Erasmus Universiteit Rotterdam, NL-3000 DR Rotterdam, The Netherlands, 6South West Thames Regional Genetics Service, St George’s Hospital Medical School, London SW17 ORE, UK, 7Institut für Humangenetik, Universitätsklinikum Essen, D-45122 Essen, Germany, 8Institut für Humangenetik, Johann Wolfgang Goethe-Universität, D-60590 Frankfurt, Germany, 9Institut für Humangenetik, Virchow-Klinikum, Humboldt-Universität, D-13353 Berlin, Germany, 10Abteilung Medizinische Genetik, Altonaer Kinderkrankenhaus, D-22763 Hamburg, Germany, 11Säuglingsklinik, Klinikum Chemnitz, D-09009 Chemnitz, Germany, 12Institut für Humangenetik, Universität Leipzig, D-04103 Leipzig, Germany and 13Kinderspital Zürich, Universitäts-Kinderklinik, CH-8032 Zürich, Switzerland

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister–Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient’s GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA1 and TA2) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

+ To whom correspondence should be addressed. Tel: +49 6421 286232; Fax: +49 6421 288920; Email: grzeschi{at}mailer.uni-marburg.de


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