Disease relevance of DKC1

• The identification of dyskeratosis congenita gene 1 (DKC1) mutations in X-linked recessive patients initially suggested that DC is a defective pseudouridylation disorder [1].
• We report a novel missense mutation in DKC1 exon 3 (T113-->C, Ile38Thr) in a Sardinian infant with XL-HHS in whom the disease was characterized by 'T+B-NK-' severe combined immunodeficiency and bone marrow failure [2].
• DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer [3].
• Therefore, in this study, the distribution of dyskerin in a large series of human tumours from the lung, breast, and colon, as well as from B-cell lymphomas, was analysed by immunohistochemistry [4].
• A quantitative analysis of dyskerin mRNA expression was then performed in 70 breast carcinomas together with the evaluation of telomerase RNA component levels and rRNA pseudo-uridylation [4].

Psychiatry related information on DKC1

• We speculated that mutations in the gene responsible for X-linked DC (DKC1) may account for the HH syndrome, due to the phenotypic similarities between the disease in respect of AA and gender bias [5].

High impact information on DKC1

• The close homolog Cbf5/dyskerin is the catalytic subunit of box H/ACA snoRNPs [6].
• Five different missense mutations in five unrelated patients were subsequently identified in XAP101, indicating that it is the gene responsible for X-linked DKC (DKC1) [7].
• The peptide dyskerin contains two TruB pseudouridine (psi) synthase motifs, multiple phosphorylation sites, and a carboxy-terminal lysine-rich repeat domain [7].
• The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA [8].
• Here we show that dyskerin is associated not only with H/ACA small nucleolar RNAs, but also with human telomerase RNA, which contains an H/ACA RNA motif [9].

Chemical compound and disease context of DKC1

• By extrapolation, our findings also support the assignment of pseudouridine synthase function to certain physiologically important eukaryotic proteins that contain Motif I, including the human protein dyskerin, alteration of which leads to the disease dyskeratosis congenita [10].

Biological context of DKC1

• Mutations in DKC1 mainly lead to amino acid substitutions [11].
• Dyskerin is therefore thought to function in the processing of pre-rRNA and of the hTR, strengthening the notion that the underlying mechanism of DKC is a premature senescence of cells, especially of the rapidly dividing epithelial and hemopoietic cells [12].
• We have determined the genomic structure of the DKC1 gene; it consists of 15 exons spanning a region of 15 kb [13].
• The affected boy had an unaffected brother with the same haplotype around the DKC1 gene and a sister who was heterozygous for the deletion [14].
• Normal levels of mRNA are produced from the deleted gene, with the transcripts using a cryptic polyadenylation site in the antisense strand of the adjacent MPP1 gene, normally located 1 kb downstream of DKC1 in a tail to tail orientation [14].

Anatomical context of DKC1

• In addition, higher level Dkc1 expression was confined to embryonic neural tissues as well as to specific neurons in the cerebellum (Purkinje cells) and the olfactory bulb (mitral cells) of the adult brain [12].
• X-linked dyskeratosis congenita (DC) is a bone marrow failure syndrome caused by mutations in the DKC1 gene located at Xq28 [14].
• The gene responsible for X-linked DC (DKC1) encodes a highly conserved protein called dyskerin that is believed to be essential in ribosome biogenesis and may also be involved in telomerase RNP assembly [15].
• Dyskerin gene silencing in the MCF-7 human breast carcinoma cell line reduced telomerase activity and rRNA pseudo-uridylation [4].
• To test the extent to which disruption of pseudouridylation or telomerase activity may contribute to the pathogenesis of DC, we introduced two dyskerin mutations into murine embryonic stem cells [16].

Associations of DKC1 with chemical compounds

• Only his mother's DNA was available for mutation analysis, which revealed a nucleotide transition of C to T (1058 C --> T), a hotspot mutation in DKC, resulting in an amino acid change from alanine to valine (A353V) in the DKC1 gene [17].
• Dyskerin is a putative pseudouridine synthase, and it has been suggested that DKC may be caused by a defect in ribosomal RNA processing [9].
• Sequencing of the DKC1 gene revealed an inherited missense mutation in base 1050 (GC), changing methionine to isoleucine [18].
• Dyskerin associates with the H/ACA class of small nucleolar RNAs which are important in guiding the conversion of uracil to pseudouracil in ribosomal RNA [19].

Regulatory relationships of DKC1

• Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer [4].

Other interactions of DKC1

• The DKC1-encoded protein, dyskerin, is a component of small nucleolar ribonucleoprotein particles, which are important in ribosomal RNA processing, and of the telomerase complex [20].
• X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene [13].
• Immunoglobulin-tagged dyskerin did not interact with the Fanconi anemia group A protein, FANCA [21].

Analytical, diagnostic and therapeutic context of DKC1

• RNA in situ hybridizations on day 10.5-18.5 postconception embryos showed a ubiquitous expression of Dkc1 with a notably higher level of expression confined to the epithelial tissues [12].
• A novel DKC1 mutation, severe combined immunodeficiency (T+B-NK- SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome [2].
• The 15 coding exons of DKC1 and their flanking regions were amplified from genomic DNA by PCR [22].

References