The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita

Abstract

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. 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. Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.

Telomere and telomerase in stem cells

“…Bone marrow insufficiency in a telomerasedeficient disease, DKC (Vulliamy et al, 2001), may be further evidence of that. Telomerase activity appears to be upregulated in response to cytokine-induced proliferation and cell cycle activation in primitive HSCs, and progressively downregulated in more matured subsets (Chiu et al, 1996) except for mitogenically activated lymphocytes (Hiyama et al, 1995) (Figure 1).…”

“…Positional cloning identified the gene affected in many patients with X-linked DKC as the human homologue of yeast CBF5, termed DKC1, encoding a protein, dyskerin. The association of the telomerase complex with dyskerin suggested that the DKC phenotype may be the result of altered telomerase activity (Vulliamy et al, 2001). Then, the discovery of a 3 0 deletion in the gene encoding TERC in a single large family with autosomal dominant DKC confirmed the importance of telomerase deficiency as the aetiology for DKC and highlighted the importance of telomerase in maintaining cellular lifespan and replicative potential in human organs.…”

Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC

“…Mutations in dyskerin, which is involved in ribosomal RNA processing 3 and in the telomerase complex 4 , are responsible for the X-linked form of this disease 5 . Families with autosomal dominant inheritance of dyskeratosis congenita (AD-DC) have mutations in the gene encoding the RNA component of telomerase (TERC) 6 . These mutations seem to give rise to the disease through haploinsufficiency, through the absence of a 3′ end, impaired RNA accumulation or a catalytic defect 7 .…”

“…In these families, affected individuals are heterozygous with respect to mutations in TERC. Three of the eight families and the mutations they carry were previously described 6 : family DCR063 (408C→G), family DCR082 (107-108GC→AG) and family DCR101 (3′ deletion, from nucleotide 378 onward). In two of the eight families, the index case presented with aplastic anemia: family DCR172 (72C→G) and family DCR174 (110-113 deletion GACT) 8 .…”

Nouvelles formes de dyskératoses congénitales

“…Le lien entre DC et dysfonctionnement télomérique s'est trouvé renforcé par l'identification de mutations dans d'autres composantes du complexe télomérase dont la matrice ARN hTERC [14]. Des délétions de hTERC sont responsables des formes autosomiques dominantes de DC.…”