Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1254-1260
Dyskeratosis Congenita Caused by a 3' Deletion: Germline and
Somatic Mosaicism in a Female Carrier
T.J. Vulliamy,
S.W. Knight,
N.S. Heiss,
O.P. Smith,
A. Poustka,
I. Dokal, and
P.J. Mason
From the Department of Haematology, Imperial College School of
Medicine, Hammersmith Hospital, London, UK; Deutches
Krebsforschungszentrum, Department of Molecular Genome Analysis,
Heidelberg, Germany; and the Department of Paediatric Haematology,
National Childrens Hospital, Dublin, Ireland.
X-linked dyskeratosis congenita (DC) is a bone marrow failure
syndrome caused by mutations in the DKC1 gene located at Xq28. By 20 years of age, most affected boys develop bone marrow failure, whereas female carriers show a skewed pattern of X-chromosome inactivation. The gene product, dyskerin, is homologous to a yeast protein involved in ribosomal RNA biogenesis, providing a unique insight into a cause of aplastic anemia. Whereas most causative mutations are single amino acid substitutions, and nonsense or frameshift mutations have not been observed, we present here a case of
DC caused by a 2-kb deletion that removes the last exon of the gene.
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. The predicted truncated protein lacks a lysine-rich peptide that is less conserved than the rest of the dyskerin molecule and is dispensable in yeast, supporting the contention that it may retain some activity and that
null mutations at this locus may be lethal. The affected boy had an
unaffected brother with the same haplotype around the DKC1 gene
and a sister who was heterozygous for the deletion. We conclude
therefore that the mother must be a germline mosaic with respect to
this deletion. Investigation of her blood cells and other somatic
tissues showed that a small proportion of these cells also carried the
deletion, making her a somatic mosaic and indicating that the deletion
took place early in development.
