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

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that i s characterized by abnormal skin pigmentation, leukoplakia and nail dystrop hy(1,2). X-linked, autosomal recessive and autosomal dominant inheritance h ave 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 p rotein that is found associated with the H/ACA class of small nucleolar RNA s and is involved in pseudo-uridylation of specific residues of ribosomal R NA(4). Dyskerin is also associated with telomerase RNA (hTR)(5), which cont ains a H/ACA consensus sequence(6,7). Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inherita nce. Affected members of this family have an 821-base-pair deletion on chro mosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.