Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation

Abstract

The two genes mutated in the bone marrow failure syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC. (Blood.

Physiological assembly and activity of human telomerase complexes

“…Patients with the X-linked form of dyskeratosis congenita (DC) harbor small changes in the gene encoding dyskerin (Vulliamy et al, 2006). Young males who inherit a mutant dyskerin gene on their X-chromosome suffer progressive, fatal bone marrow failure.…”

“…The scope of disease known to result from telomerase deficiency extends beyond DC to include aplastic anemia, pulmonary fibrosis, Hoyeraal-Hreidarsson syndrome and cancer (Vulliamy et al, 2006). These diverse clinical presentations are just an inkling of the much greater phenotypic diversity that may be linked to telomere maintenance deficiency in the future.…”

Protein universe containing a PUA RNA‐binding domain

“…These mutations cause a reduction in telomerase activity, leading to limitations in the proliferative capacity of stem cells. This reduction in proliferative capacity for high turnover cells leads to low counts for blood and immune cells, resulting in aplastic anemia [44]. Like all small nucleolar RNP-associated proteins, dyskerin is phylogenetically highly conserved, and is found in all studied species.…”

The role of telomere biology in bone marrow failure and other disorders

“…Additional features include epiphora, blepharitis, premature gray hair, alopecia, developmental delay, short stature, cerebellar hypoplasia, microcephaly, esophageal stenosis, urethral stenosis, pulmonary fibrosis, liver disease, avascular necrosis of hips or shoulders, epithelial cancers, myelodysplastic syndrome (MDS), and leukemia (Alter 2005;Walne et al 2005;Yamaguchi 2007). Hoyeraal-Hreidarsson (HH) Syndrome is a severe form of DC with BMF, immunodeficiency, microcephaly, cerebellar hypoplasia, intrauterine growth retardation, and developmental delay (Sznajer et al 2003;Vulliamy et al 2006). Revesz Syndrome, characterized by bilateral exudative retinopathy, bone marrow hypoplasia, nail dystrophy, fine hair, cerebellar hypoplasia, and growth retardation, also appears to be in the DC disease spectrum (Kajtar and Mehes 1994;Revesz et al 1992).…”