CEBPA was first reported in relation to autosomal dominant acute myeloid leukemia in 2004 (Smith et al., 2004 PMID: 15575056). At least 16 unique variants (primarily frameshift but also missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.
Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 16 probands in 11 publications (PMIDs: 21455213, 30563700, 23716546, 21177436, 26162409, 19953636, 18946494, 18768433, 15902292, 15575056, 26721895). Variants in this gene segregated with disease in 15 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism for disease is primarily through a dominant negative effect. N-terminal frameshift mutations cause truncation of the 42-kD CEBPA protein and overproduction of a 30-kD which functions in a dominant negative fashion (Pabst et al., 2001 PMID: 11242107). A small set of variants have also been identified near the C-terminal end, in the basic leucine zipper region, which is predicted to disrupt the DNA binding and dimerization of CEBPA.
EXPERIMENTAL EVIDENCE: 4 points This gene-disease association is supported by functional alteration of its biochemical function, its expression, and animal models. CEBPA functions as a myeloid transcription factor, acting as an important mediator of granulocytic maturation (Wang et al., 1999 PMID: 10397723). This is supported by the expression of CEBPA both in normal development and during malignancy (Scott et al., 1992 PMID: 1391942). This role in granulocytic maturation is disrupted by N-terminal frameshift mutations, as observed in non-patient H1299 cells (Pabst et al., 2008 PMID: 18768433). This is supported by mice carrying engineered Cebpa alleles, that specifically disrupt the 42-kDa wild-type protein while allowing expression of the dominant-negative 30-kDa form, which led to development of AML with complete penetrance (Kirstetter et al., 2008 PMID: 18394553).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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