X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

Abstract

Dyskeratosis congenita is a rare inherited bone marrow-failure syndrome characterized by abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. More than 80% of patients develop bone-marrow failure, and this is the major cause of premature death. The X-linked form of the disease (MIM 305000) has been shown to be caused by mutations in the DKC1 gene. The gene encodes a 514-amino-acid protein, dyskerin, that is homologous to Saccharomyces cerevisiae Cbf5p and rat Nap57 proteins. By analogy to the homologues in other species, dyskerin is predicted to be a nucleolar protein with a role in both the biogenesis of ribosomes and, in particular, the pseudouridylation of rRNA precursors. We have determined the genomic structure of the DKC1 gene; it consists of 15 exons spanning a region of 15 kb. This has enabled us to screen for mutations in the genomic DNA, by using SSCP analysis. Mutations were detected in 21 of 37 additional families with dyskeratosis congenita that were analyzed. These mutations consisted of 11 different single-nucleotide substitutions, which resulted in 10 missense mutations and 1 putative splicing mutation within an intron. The missense change A353V was observed in 10 different families and was shown to be a recurring de novo event. Two polymorphisms were also detected, one of which resulted in the insertion of an additional lysine in the carboxy-terminal polylysine domain. It is apparent that X-linked dyskeratosis congenita is predominantly caused by missense mutations; the precise effect on the function of dyskerin remains to be determined.

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

“…19 Mutation of DKC1 leads to a diseased condition known as X-linked dyskeratosis congentita, which is characterized by abnormal pigmentation, bone marrow failure and an increased susceptibility to cancer. 38,39 Recently, Cayuela et al 40 has shown in transgenic TERT/ TERC À/À mice that the increased expression of TERT, in the absence of TERC genetic background, leads to reduced tumorigenesis, indicating that the tumor-promoting effects of TERT overexpression require the formation of TERT-TERC complexes. In this regard, we propose that rAAVhTERTC27-mediated downregulation of DKC1 may lead to abnormal processing and/or trafficking of hTERTC, which in turn result in telomere destabilization and eventually senescence and apoptosis in the glioblastoma tissues.…”

Haploinsufficiency of t e lomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita

“…These latter phenotypes, although clinically asymptomatic, often appear first as fatal complications of treatment in the setting of bone marrow transplant and are related to hypersensitivity to preparative chemotherapy and radiation regimens (1,2). The X-linked form of DC presents in the first decade, is most severe, and is a result of mutations in the DKC1 gene (3). The autosomal dominant (AD) form of DC is rare, has a later presentation, and is characterized by mutations in telomerase RNA (hTR) (4).…”

Identification of a novel mutation in DKC1 in dyskeratosis congenita

“…The majority of mutations in DKC1 are missense, and only three non-missense mutations are known: a single amino acid deletion (mentioned above), a deletion of the last exon of the gene and a mutation affecting differential splicing of the mRNA [2,5]. To our knowledge, c.166_167invCT is a novel mutation involving a small inversion in DKC1 gene.…”

“…The majority of the disease-causing mutations are single amino acid substitutions. The substitution A353V has been observed in $30% of X-linked families, frequently as a de novo mutation [2]. Here, we report a Russian pedigree with X-linked DC and a novel mutation of the DKC1 gene.…”

“…All samples were obtained with appropriate consent. Mutation screening for DKC1 genomic DNA was performed using designed primers for exons 7, 10, 13, and 15, and primers described by Knight et al [2] for other exons (1-6, 8-9, 11-12, 14). Each of the 15 exons of the DKC1 gene, together with flanking intronic regions, was amplified and analyzed for mutations by SSCP [3].…”