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

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Abstract
Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy1,2. 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 RNA4. Dyskerin is also associated with telomerase RNA (hTR)5, which contains a H/ACA consensus sequence6,7. 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.