Dyskeratosis Congenita Caused by a 3′ Deletion: Germline and Somatic Mosaicism in a Female Carrier

• Published in: Blood Vol. 94; no. 4; pp. 1254 - 1260
• Main Authors: Vulliamy, T.J., Knight, S.W., Heiss, N.S., Smith, O.P., Poustka, A., Dokal, I., Mason, P.J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.08.1999; The Americain Society of Hematology
• Subjects: 3' Untranslated Regions - genetics; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Cell Cycle Proteins - genetics; Dyskeratosis Congenita - genetics; Female; Germ-Line Mutation; Haplotypes; Hematologic and hematopoietic diseases; Humans; Male; Medical sciences; Molecular Sequence Data; Nuclear Proteins - genetics; Other diseases. Hematologic involvement in other diseases; Pedigree; Sequence Deletion; X Chromosome; Chromosomal aberration; Human; Skin disease; Pigmentation disorder; Stomatology; Abnormal X chromosome; Family study; Hyperkeratosis; Hemopathy; Genetic disease; Somatic mutation; Gene; Germ line; Cytogenetics; Deletion; Abnormal chromosome; Genetics; Adult; Dyskeratosis congenita; Female; Mosaicism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.4.1254

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.