A telomerase component is defective in the human disease dyskeratosis congenita

Abstract

The X-linked form of the human disease dyskeratosis congenita (DKC) is caused by mutations in the gene encoding dyskerin. Sufferers have defects in highly regenerative tissues such as skin and bone marrow, chromosome instability and a predisposition to develop certain types of malignancy. Dyskerin is a putative pseudouridine synthase, and it has been suggested that DKC may be caused by a defect in ribosomal RNA processing. Here we show that dyskerin is associated not only with H/ACA small nucleolar RNAs, but also with human telomerase RNA, which contains an H/ACA RNA motif. Telomerase adds simple sequence repeats to chromosome ends using an internal region of its RNA as a template, and is required for the indefinite proliferation of primary human cells. We find that primary fibroblasts and lymphoblasts from DKC-affected males are not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function; however, DKC cells have a lower level of telomerase RNA, produce lower levels of telomerase activity and have shorter telomeres than matched normal cells. The pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood.

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

“…23 A prime candidate gene for this X-linked mechanism is DKC1 encoding dyskerin, which is important for the function of telomerase and has been found to cause congenital dyskeratosis that is characterized by short telomeres. 43 However, if an X-linked mechanism is in effect, a Relationship a n r P -value n r P -value n r P -value n r P -value n r P -value Family effects in telomere length L Broer et al stronger father-daughter correlation would be expected, compared with the father-son correlation, which we did not observe. Other potential explanations for the larger mother-offspring correlation include mitochondrial DNA or other parent-specific 'imprinting' .…”

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

“…These genes could be categorized into nine groups based on their predicted functions, namely those involved in apoptosis, cell cycle, immune response, telomere maintenance, cell adhesion, transport, metabolism, signal transduction and transcription (Figure 5a). Expression levels of representative genes from various functional categories including dyskeratosis congenital 1 gene (DKC1), 19 target of methylation-induced silencing 1 (TMS1), 20 regulatory factor X-associated protein (RFXAP), 21 NCAM1, 22 and SOCS1 23 were validated by semiquantitative RT-PCR. In general, the RT-PCR data were consistent with the microarray data ( Figure 5b and c and Table 2).…”

“…DKC1 is crucial for telomere maintenance because it is required for the correct intranuclear trafficking of hTERC (or hTR), the RNA component of the hTERT holoenzyme. 19 Mutation of DKC1 leads to a diseased condition known as X-linked dyskeratosis congentita, which is characterized by abnormal pigmentation, bone marrow failure and an increased susceptibility to cancer. 38,39 Recently, Cayuela et al 40 has shown in transgenic TERT/ TERC À/À mice that the increased expression of TERT, in the absence of TERC genetic background, leads to reduced tumorigenesis, indicating that the tumor-promoting effects of TERT overexpression require the formation of TERT-TERC complexes.…”

Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC

“…Mutations in dyskerin, which is involved in ribosomal RNA processing 3 and in the telomerase complex 4 , are responsible for the X-linked form of this disease 5 . Families with autosomal dominant inheritance of dyskeratosis congenita (AD-DC) have mutations in the gene encoding the RNA component of telomerase (TERC) 6 .…”