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N-Terminal Variant p.Ala2Val in X-Linked Dyskeratosis Congenita Gene (DKC1) Disrupts Its Post-Translational Modification and Nucleolar Localization
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N-Terminal Variant p.Ala2Val in X-Linked Dyskeratosis Congenita Gene (DKC1) Disrupts Its Post-Translational Modification and Nucleolar Localization

Taimoor I Sheikh and John B Vincent
Molecular genetics & genomic medicine, v 14(8), e70273
Aug 2026
DOI: https://doi.org/10.1002/mgg3.70273
PMID: 42592823
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https://doi.org/10.1002/mgg3.70273View
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Abstract

Cell Cycle Proteins - chemistry Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Nucleolus - metabolism Dyskeratosis Congenita - genetics Dyskeratosis Congenita - metabolism Dyskeratosis Congenita - pathology HEK293 Cells Humans Mutation, Missense Nuclear Proteins - chemistry Nuclear Proteins - genetics Nuclear Proteins - metabolism Protein Processing, Post-Translational
Dyskeratosis congenita (DKC) is typically characterized by the triad of abnormal cutaneous pigmentation, nail dystrophy, and oral mucosal leukoplakia. Progressive bone marrow failure develops in over 80% of cases and constitutes the leading cause of early mortality. Pathogenic variants in DKC1 have been associated with a high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. The DKC1 missense variant, c.5C>T, leading to p.(Ala2Val), has been reported in families affected with dyskeratosis congenita. However, due to lack of functional analysis, it remains a variant of uncertain significance (VUS). Here, we performed functional analysis of the DKC1 gene product to investigate the pathophysiology of DKC1-related dyskeratosis congenita. We performed co-localization studies of HEK293T cells transfected with GFP-tagged constructs encoding either a wild-type (WT) or p.(Ala2Val) human DKC1 protein, along with Liquid Chromatography Mass Spectrometry (LCMS) of immunoprecipitated (IP) WT or p.(Ala2Val) DKC1 protein to study post-translation modification status. We have shown that p.(Ala2Val) DKC1 leads to mis-localization of the protein from the nucleolus to the nucleoplasm. Also, LCMS showed that N-terminal methionine cleavage occurs for both, but N-acetylation occurs for WT but not for p.(Ala2Val) DKC1. The mis-localization and altered post-translational modification of p.(Ala2Val) DKC1 provides functional evidence to clinical laboratories to reclassify p.(Ala2Val) variant as "pathogenic" as per American College of Medical Genetics (ACMG) variant interpretation guidelines.

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