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Variable expression of Dkc1 mutations in mice
Jun He1, Bai-Wei Gu, Jingping Ge
1Department of Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
In humans mutations in DKC1, cause the rare bone marrow failure syndrome dyskeratosis congenita. We have used gene targeting to produce mouse ES cells with Dkc1 mutations that cause DC when in humans. The mutation A353V, the most common human mutation, causes typical DC to very severe DC in humans. Male chimeric mice carrying this mutation do not pass the mutated allele to their offspring. The mutation G402E accounts for a single typical case of DC in a human family. The allele carrying this mutation was transmitted to the offspring with high efficiency. Expression of RNA and protein was reduced compared to wild type animals, but no abnormalities of growth and development or in blood values were found in mutant mice. Thus Dkc1 mutations have variable expression in mice, as in humans.
Insights
Mutations in the DKC1 gene cause dyskeratosis congenita (DC). Mouse models show that DKC1 mutations have variable expression, similar to human patients, impacting disease severity and inheritance.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Mutations in the DKC1 gene are linked to the rare bone marrow failure syndrome, dyskeratosis congenita (DC).
- Understanding the impact of specific DKC1 mutations is crucial for elucidating DC pathogenesis.
Purpose of the Study:
- To generate and characterize mouse models with specific DKC1 mutations found in human dyskeratosis congenita.
- To investigate the variable expressivity and inheritance patterns of these Dkc1 mutations in mice.
Main Methods:
- Gene targeting in mouse embryonic stem cells to introduce human DKC1 mutations (A353V and G402E).
- Generation of chimeric mice and assessment of germline transmission of mutated alleles.
- Analysis of RNA and protein expression levels in mutant mice.
- Evaluation of growth, development, and blood parameters in mutant mice.
Main Results:
- The common human mutation A353V resulted in typical to severe DC phenotypes in mice, but was not passed to offspring by male chimeric mice.
- The human mutation G402E, associated with a single DC case, was efficiently transmitted to offspring.
- Mice with the G402E mutation showed reduced RNA and protein expression but no overt growth, developmental, or hematological abnormalities.
Conclusions:
- DKC1 mutations exhibit variable expressivity in mouse models, mirroring observations in human dyskeratosis congenita.
- The mouse models developed provide valuable tools for studying the mechanisms underlying DC and the influence of specific mutations.
