Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Details

Serval ID
serval:BIB_EB411BEFB643
Type
Article: article from journal or magazin.
Collection
Publications
Title
Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.
Journal
Human Molecular Genetics
Author(s)
Kalff-Suske M., Wild A., Topp J., Wessling M., Jacobsen E.M., Bornholdt D., Engel H., Heuer H., Aalfs C.M., Ausems M.G., Barone R., Herzog A., Heutink P., Homfray T., Gillessen-Kaesbach G., König R., Kunze J., Meinecke P., Müller D., Rizzo R., Strenge S., Superti-Furga A., Grzeschik K.H.
ISSN
0964-6906 (Print)
ISSN-L
0964-6906
Publication state
Published
Issued date
1999
Volume
8
Number
9
Pages
1769-1777
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
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 (TA(1)and TA(2)) 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.
Keywords
Animals, Craniofacial Abnormalities/genetics, DNA Mutational Analysis, DNA-Binding Proteins/genetics, Drosophila, Humans, Kruppel-Like Transcription Factors, Limb Deformities, Congenital/genetics, Mutation, Nerve Tissue Proteins, Recombinant Fusion Proteins, Repressor Proteins, Sequence Deletion, Syndrome, Transcription Factors/genetics, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Xenopus Proteins, Zinc Fingers/genetics
Pubmed
Web of science
Create date
14/03/2011 16:14
Last modification date
20/08/2019 16:13
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