Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Base Sequence
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Blood Platelets / metabolism
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Chromosome Mapping
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Colony-Forming Units Assay
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Core Binding Factor Alpha 2 Subunit
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DNA Mutational Analysis
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DNA-Binding Proteins*
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Family Health
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Female
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Genetic Predisposition to Disease
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Genotype
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Hematopoiesis / genetics
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Heterozygote
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Humans
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In Situ Hybridization, Fluorescence
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Leukemia, Myeloid, Acute / genetics*
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Male
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Megakaryocytes / cytology
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Megakaryocytes / metabolism
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Microsatellite Repeats
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Molecular Sequence Data
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Mutation
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Pedigree
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Proto-Oncogene Proteins*
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RNA / genetics
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RNA / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Deletion
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Sequence Homology, Amino Acid
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Sequence Homology, Nucleic Acid
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Thrombocytopenia / genetics*
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Transcription Factors / genetics*
Substances
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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Proto-Oncogene Proteins
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RUNX1 protein, human
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Transcription Factors
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RNA
Associated data
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GENBANK/AJ229041
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GENBANK/AJ229042
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GENBANK/AJ229043
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GENBANK/AP000032
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GENBANK/AP000033
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GENBANK/AP000034
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GENBANK/AP000035
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GENBANK/AP000036
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GENBANK/AP000037
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GENBANK/AP000038
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GENBANK/AP000039
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GENBANK/AP000040
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GENBANK/AP000041
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GENBANK/AP000042
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GENBANK/AP000043
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GENBANK/AP000044
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GENBANK/AP000045
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GENBANK/AP000046
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GENBANK/AP000047
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GENBANK/AP000048
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GENBANK/AP000049
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GENBANK/AP000050
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GENBANK/AP000051
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GENBANK/AP000052
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GENBANK/AP000053
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GENBANK/AP000054
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GENBANK/AP000055
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GENBANK/AP000056
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GENBANK/AP000057