Nature genetics, 1999-10, Vol.23 (2), p.166-175
- Gilliland, D. Gary
- Song, Woo-Joo
- Sullivan, Melanie G
- Legare, Robert D
- Hutchings, Sarah
- Tan, Xiaolian
- Kufrin, Dubravka
- Ratajczak, Janina
- Resende, Isabel C
- Haworth, Catherine
- Hock, Randy
- Loh, Mignon
- Felix, Carolyn
- Roy, Denis-Claude
- Busque, Lambert
- Kurnit, David
- Willman, Cheryl
- Gewirtz, Alan M
- Speck, Nancy A
- Bushweller, John H
- Li, Frederick P
- Gardiner, Katheleen
- Poncz, Mortimer
- Maris, John M
1999
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- Autor(en) / Beteiligte
- Gilliland, D. Gary
- Song, Woo-Joo
- Sullivan, Melanie G
- Legare, Robert D
- Hutchings, Sarah
- Tan, Xiaolian
- Kufrin, Dubravka
- Ratajczak, Janina
- Resende, Isabel C
- Haworth, Catherine
- Hock, Randy
- Loh, Mignon
- Felix, Carolyn
- Roy, Denis-Claude
- Busque, Lambert
- Kurnit, David
- Willman, Cheryl
- Gewirtz, Alan M
- Speck, Nancy A
- Bushweller, John H
- Li, Frederick P
- Gardiner, Katheleen
- Poncz, Mortimer
- Maris, John M
- Titel
- Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia
- Ist Teil von
- Nature genetics, 1999-10, Vol.23 (2), p.166-175
- Ort / Verlag
- London: Nature Publishing Group
- Erscheinungsjahr
- 1999
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036eISSN: 1546-1718DOI: 10.1038/13793Titel-ID: cdi_proquest_miscellaneous_70798276
- Format
- –
- Schlagworte
- Amino Acid Sequence, Base Sequence, Biological and medical sciences, Blood Platelets - metabolism, Chromosome Mapping, Colony-Forming Units Assay, Core Binding Factor Alpha 2 Subunit, DNA Mutational Analysis, DNA-Binding Proteins, Family Health, Female, Genetic Predisposition to Disease, Genotype, Hematologic and hematopoietic diseases, Hematopoiesis - genetics, Heterozygote, Humans, In Situ Hybridization, Fluorescence, Leukemia, Myeloid, Acute - genetics, Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis, Male, Medical sciences, Megakaryocytes - cytology, Megakaryocytes - metabolism, Microsatellite Repeats, Molecular Sequence Data, Mutation, Pedigree, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, RNA - genetics, RNA - metabolism, Sequence Deletion, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Thrombocytopenia - genetics, Transcription Factors - genetics