Abstract
Dyskeratosis congenita (DC) is a severe inherited premature aging syndrome characterised by muco-cutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. X-linked recessive, autosomal dominant (AD) and autosomal recessive (AR) forms of the disease are recognised. Mutations in DKC1 and TERC have been identified in X-linked recessive and AD-DC, respectively. The products encoded by both of these genes are key components of the telomerase complex, which is responsible for maintaining telomere length after cell division. This has led to the suggestion that DC is primarily a disease of defective telomere maintenance. The international dyskeratosis congenita registry (Hammersmith Hospital, London) has information on 244 families with DC. Of these 30% have mutations in DKC1 and 6% have mutations in TERC. Disease causing mutations in the remaining 64% of patients have yet to be characterised. In an attempt to identify a candidate locus through homozygosity mapping, we performed a genome-wide scan using a maximum of 475 microsatellite markers (LMS-MD 10/5 ABI PRISM) on DNA from 19 affected individuals from 13 families with consanguineous marriage. No single marker was found to be homozygous in all individuals, although not all markers were typed in all individuals. 19% of markers were homozygous in four or more families across the chromosomes, but this dropped to 4% when the number of families that were homozygous was increased to six. Only six markers (1% approx.) were homozygous in seven or more families. This suggests there is considerable genetic heterogeneity amongst the AR-DC subset. To investigate this further we selected one family that showed a recessive pattern of inheritance with samples available from three affected individuals, three unaffected siblings and parents. Affected members in this family had the classical DC features of nail dystrophy, abnormal skin pigmentation, abnormal dentition and severe bone marrow failure in the index case. To try to identify a disease locus in this family, we typed the whole family at the markers where the affected individuals shared common homozygosity and analysed the data using Genehunter, a multi-point linkage analysis program, to obtain a LOD score (log10 of the odd ratio in favour of linkage). The maximum LOD score obtained for this family was 2.7 on chromosome 15, suggesting that a disease-causing locus is at chromosome 15q14. This particular location seems to be unique to this family as there is no overlap in homozygosity with any other family studied. It remains to be established how many loci there are, and whether a single gene causes DC in many of the AR families, or if each gene identified causes the disease in a small subset of families. In conclusion this work highlights the extent of genetic heterogeneity that exists in DC, with AR-DC being a very heterogeneous subtype which may involve several genes, but the locus of one AR-DC gene has been assigned to chromosome 15q14.
Genome-wide linkage analysis of an autosomal recessive hypotrichosis identifies a novel P2RY5 mutation