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1.  Single Nucleotide Polymorphism Array Analysis of Bone Marrow Failure Patients Reveals Characteristic Patterns of Genetic Changes 
British journal of haematology  2013;164(1):73-82.
Summary
The bone marrow failure syndromes (BMFS) are a heterogeneous group of rare blood disorders characterized by inadequate haematopoiesis, clonal evolution, and increased risk of leukaemia. Single nucleotide polymorphism arrays (SNP-A) have been proposed as a tool for surveillance of clonal evolution in BMFS. To better understand the natural history of BMFS and to assess the clinical utility of SNP-A in these disorders, we analysed 124 SNP-A from a comprehensively characterized cohort of 91 patients at our BMFS centre. SNP-A were correlated with medical histories, haematopathology, cytogenetic and molecular data. To assess clonal evolution, longitudinal analysis of SNP-A was performed in 25 patients. We found that acquired copy number-neutral loss of heterozygosity (CN-LOH) was significantly more frequent in acquired aplastic anaemia (aAA) than in other BMFS (odds ratio 12.2, p<0.01). Homozygosity by descent was most common in congenital BMFS, frequently unmasking autosomal recessive mutations. Copy number variants (CNVs) were frequently polymorphic, and we identified CNVs enriched in neutropenia and aAA. Our results suggest that acquired CN-LOH is a general phenomenon in aAA that is probably mechanistically and prognostically distinct from typical CN-LOH of myeloid malignancies. Our analysis of clinical utility of SNP-A shows the highest yield of detecting new clonal haematopoiesis at diagnosis and at relapse.
doi:10.1111/bjh.12603
PMCID: PMC3986350  PMID: 24116929
bone marrow failure; aplastic anaemia; chromosomal rearrangements; clonal evolution; cytogenetic diagnosis
2.  Acquired Aplastic Anemia in Children 
Pediatric clinics of North America  2013;60(6):1311-1336.
SYNOPSIS
This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.
doi:10.1016/j.pcl.2013.08.011
PMCID: PMC3894991  PMID: 24237973
Acquired aplastic anemia; Bone marrow failure; Immune-mediated aplastic anemia; Immune suppressive therapy for severe aplastic anemia in children; Bone marrow transplant for severe aplastic anemia in children
3.  Common polymorphic deletion of glutathione S-transferase theta predisposes to acquired aplastic anemia: Independent cohort and meta-analysis of 609 patients 
American journal of hematology  2013;88(10):862-867.
Acquired aplastic anemia (AA) is a rare life-threatening bone marrow failure syndrome, caused by autoimmune destruction of hematopoietic stem and progenitor cells. Epidemiologic studies suggest that environmental exposures and metabolic gene polymorphisms contribute to disease pathogenesis. Several case–control studies linked homozygous deletion of the glutathione S-transferase theta (GSTT1) gene to AA; however, the role of GSTT1 deletion remains controversial as other studies failed to confirm the association. We asked whether a more precise relationship between the GSTT1 null polymorphism and aplastic anemia could be defined using a meta-analysis of 609 aplastic anemia patients, including an independent cohort of 67 patients from our institution. We searched PubMed, Embase, and the Cochrane Database for studies evaluating the association between GSTT1 null genotype and development of AA. Seven studies, involving a total of 609 patients and 3,914 controls, fulfilled the eligibility criteria. Meta-analysis revealed a significant association of GSTT1 null genotype and AA, with an OR = 1.74 (95% CI 1.31–2.31, P< 0.0001). The effect was not driven by any one individual result, nor was there evidence of significant publication bias. The association between AA and GSTT1 deletion suggests a role of glutathione-conjugation in AA, possibly through protecting the hematopoietic compartment from endogenous metabolites or environmental exposures. We propose a model whereby protein adducts generated by reactive metabolites serve as neo-epitopes to trigger autoimmunity in aplastic anemia.
doi:10.1002/ajh.23521
PMCID: PMC3983712  PMID: 23798465
4.  Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin 
FEBS letters  2013;587(14):2112-2117.
Pseudouridine is the most abundant modified nucleotide in ribosomal RNA throughout eukaryotes and archaea but its role is not known. Here we produced mouse embryonic fibroblast cells expressing only catalytically inactive dyskerin, the pseudouridine synthase that converts uridine to pseudouridine in ribosomal RNA. The mutant dyskerin protein, D125A, was extremely unstable but cells were able to divide and grow very slowly. Abnormalities in ribosome RNA synthesis were apparent but mature cytoplasmic RNAs lacking pseudouridine were produced and were very unstable. We conclude that pseudouridine is required to stabilize the secondary structure of ribosomal RNA that is essential for its function.
Structured summary of protein interactions∷
fibrillarin and Dkc1 colocalize by fluorescence microscopy (View interaction)
doi:10.1016/j.febslet.2013.05.028
PMCID: PMC3773870  PMID: 23726835
Pseudouridine; Dyskerin; Ribosome biogenesis; snoRNA
5.  A Family with Hoyeraal-Hreidarsson Syndrome and Four Variants in Two Genes of the Telomerase Core Complex 
Pediatric blood & cancer  2013;60(6):10.1002/pbc.24389.
We describe an African American family with Hoyeraal Hreidarrson syndrome (HHS) in which 2 TERT mutations (causing P530L and A880T amino acid changes) and two in the DKC1 variants (G486R and A487A) were segregating. Both genes are associated with dyskeratosis congenita and HHS. It was important to determine the importance of these mutations in disease pathogenesis to counsel family members. From genetic analysis of family members, telomere length and X-inactivation studies we concluded that compound heterozygosity for the TERT mutations was the major cause of HHS and the DKC1 G486R variant is a rare African variant unlikely to cause disease.
doi:10.1002/pbc.24389
PMCID: PMC3860171  PMID: 23335200
aplastic anemia; bone marrow failure; dyskeratosis congenita; telomerase; telomere
6.  Using iPSCs to study Diamond Blackfan anemia: an outlook on the clinical possibilities 
Expert review of hematology  2013;6(6):627-629.
The recent development of induced human pluripotent stem cells (iPS cells) from differentiated adult cells has been heralded as potentially a major advance in medicine. iPS cells can be genetically manipulated and differentiated into a variety of adult tissues. The technology can be used to model disease pathogenesis, to screen for drugs that may be used to treat diseases and, perhaps one day, to produce healthy tissues to replace those affected by disease. Here we discuss these possibilities in the bone marrow failure syndrome Diamond Blackfan Anemia.
doi:10.1586/17474086.2013.859521
PMCID: PMC4031029  PMID: 24219546
Diamond Blackfan Anemia; iPS cells; drug discovery; pathogenesis; remission; penetrance
7.  Recent insights into inherited bone marrow failure syndromes 
Current opinion in pediatrics  2012;24(1):23-32.
Purpose of the review
Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in the last years and their impact into the understanding of IBMFS.
Recent Findings
Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development.
Summary
The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS are likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics.
doi:10.1097/MOP.0b013e32834eca77
PMCID: PMC3926810  PMID: 22227778
Inherited bone marrow failure syndromes; Fanconi Anemia; Dyskeratosis Congenita; Diamond-Blackfan Anemia; Shwachman Diamond Syndrome; Congenital Neutropenia
8.  Commentary 
Clinical chemistry  2013;59(1):51.
doi:10.1373/clinchem.2012.192302
PMCID: PMC3894990  PMID: 23284015
9.  Dysferlin and Other Non-Red Cell Proteins Accumulate in the Red Cell Membrane of Diamond-Blackfan Anemia Patients 
PLoS ONE  2014;9(1):e85504.
Diamond Blackfan Anemia (DBA) is a congenital anemia usually caused by diverse mutations in ribosomal proteins. Although the genetics of DBA are well characterized, the mechanisms that lead to macrocytic anemia remain unclear. We systematically analyzed the proteomes of red blood cell membranes from multiple DBA patients to determine whether abnormalities in protein translation or erythropoiesis contribute to the observed macrocytosis or alterations in the mature red blood cell membrane. In depth proteome analysis of red cell membranes enabled highly reproducible identification and quantitative comparisons of 1100 or more proteins. These comparisons revealed clear differences between red cell membrane proteomes in DBA patients and healthy controls that were consistent across DBA patients with different ribosomal gene mutations. Proteins exhibiting changes in abundance included those known to be increased in DBA such as fetal hemoglobin and a number of proteins not normally found in mature red cell membranes, including proteins involved in the major histocompatibility complex class I pathway. Most striking was the presence of dysferlin in the red blood cell membranes of DBA patients but absent in healthy controls. Immunoblot validation using red cell membranes isolated from additional DBA patients and healthy controls confirmed a distinct membrane protein signature specific to patients with DBA.
doi:10.1371/journal.pone.0085504
PMCID: PMC3891812  PMID: 24454878
10.  A label-free proteome analysis strategy for identifying quantitative changes in erythrocyte membranes induced by red cell disorders 
Journal of proteomics  2012;76(0 0):10.1016/j.jprot.2012.08.010.
Red blood cells have been extensively studied but many questions regarding membrane properties and pathophysiology remain unanswered. Proteome analysis of red cell membranes is complicated by a very wide dynamic range of protein concentrations as well as the presence of proteins that are very large, very hydrophobic, or heterogeneously glycosylated. This study investigated removal of other blood cell types, red cell membrane extraction, differing degrees of fractionation using 1-D SDS gels, and label-free quantitative methods to determine optimized conditions for proteomic comparisons of clinical blood samples. The results showed that fractionation of red cell membranes on 1-D SDS gels was more efficient than low-ionic-strength extractions followed by 1-D gel fractionation. When gel lanes were sliced into 30 uniform slices, a good depth of analysis was obtained that included identification of most well-characterized, low-abundance red cell membrane proteins including those present at 500 to 10,000 copies per cell. Furthermore, the size separation enabled detection of changes due to proteolysis or in vivo protein crosslinking. A combination of Rosetta Elucidator quantitation and subsequent statistical analysis enabled the robust detection of protein differences that could be used to address unresolved questions in red cell disorders.
doi:10.1016/j.jprot.2012.08.010
PMCID: PMC3508302  PMID: 22954596
11.  Acquired copy number neutral loss of heterozygosity of chromosome 7 associated with clonal haematopoiesis in a patient with Shwachman-Diamond syndrome 
British journal of haematology  2012;159(4):480-482.
doi:10.1111/bjh.12032
PMCID: PMC3484241  PMID: 22934832
Shwachman-Diamond syndrome; bone marrow failure; chromosomal rearrangements; clonal expansion; neutropenia
12.  What’s in a name? 
The Journal of Clinical Investigation  2012;122(7):2346-2349.
Mutations in numerous genes encoding ribosomal proteins (RPs) occur in 50%–70% of individuals with Diamond-Blackfan anemia (DBA), establishing the disease as a ribosomopathy. As described in this issue of JCI, Sankaran, Gazda, and colleagues used genome-wide exome sequencing to study DBA patients with no detectable mutations in RP genes. They identified two unrelated pedigrees in which the disease is associated with mutations in GATA1, which encodes an essential hematopoietic transcription factor with no known mechanistic links to ribosomes. These findings ignite an interesting and potentially emotional debate on how we define DBA and whether the term should be restricted to pure ribosomopathies. More generally, the work reflects the powerful knowledge and controversies arising from the deluge of data generated by new genetic technologies that are being used to analyze human diseases.
doi:10.1172/JCI63989
PMCID: PMC3386834  PMID: 22706300
13.  The genetics of dyskeratosis congenita 
Cancer Genetics  2011;204(12):635-645.
Dyskeratosis congenita(DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and a variable series of other somatic abnormalities. The disease is heterogeneous at the genetic and clinical levels. Determination of the genetic basis of DC has established that the disease is caused by a number of genes, all of which encode products involved in telomere maintenance, either as part of telomerase or as part of the shelterin complex that caps and protects telomeres. There is overlap at the genetic and clinical levels with other, more common conditions, including aplastic anemia (AA), pulmonary fibrosis (PF)and liver cirrhosis. Although part of the spectrum of disorders known to be associated with DC it has emerged that mutations in telomere maintenance genes can lead to the development of AA and PF in the absence of other DC features. Here we discuss the genetics of DC and its relationship to disease presentation.
doi:10.1016/j.cancergen.2011.11.002
PMCID: PMC3269008  PMID: 22285015
Bone marrow failure; telomerase; dyskerin; short telomeres; anticipation
15.  Accelerated hematopoietic stem cell aging in a mouse model of dyskeratosis congenita responds to antioxidant treatment 
Aging cell  2011;10(2):338-348.
Summary
Mutations in DKC1, encoding telomerase associated protein dyskerin, cause X-linked dyskeratosis congenita (DC), a bone marrow failure and cancer susceptibility syndrome. Decreased accumulation of telomerase RNA resulting in excessive telomere shortening and premature cellular senescence is thought to be the primary cause of disease in X-linked DC. Affected tissues are those that require constant renewal by stem cell activity. We previously showed that in Dkc1Δ15 mice, which contain a mutation that is a copy of a human mutation causing DC, mutant cells have a telomerase dependent proliferative defect and increased accumulation of DNA damage in the first generation before the telomeres are short. We now demonstrate the presence of the growth defect in Dkc1Δ15 mouse embryonic fibroblasts in vitro and show that accumulation of DNA damage and levels of reactive oxygen species increase with increasing population doublings. Treatment with the antioxidant, N-acetyl cysteine, partially rescued the growth disadvantage of mutant cells in vitro and in vivo. Competitive bone marrow repopulation experiments showed that the Dkc1Δ15 mutation is associated with a functional stem cell defect that becomes more severe with increasing age, consistent with accelerated senescence, a hallmark of DC hematopoiesis. This stem cell phenotype was partially corrected by N-acetyl cysteine treatment. These results suggest that a pathogenic Dkc1 mutation, accelerates stem cell aging, that increased oxidative stress might play a role in the pathogenesis of X-linked DC, and that some manifestations of DC may be prevented or delayed by antioxidant treatment.
doi:10.1111/j.1474-9726.2011.00674.x
PMCID: PMC3238467  PMID: 21241452
dyskeratosis congenita; N-acetyl cysteine; Stem cell aging; telomerase; oxidative stress; ROS
16.  Cytokinesis failure and attenuation: new findings in Fanconi anemia 
The hallmarks of the rare inherited disorder Fanconi anemia (FA) are progressive bone marrow failure and susceptibility to cancer. The former is the major cause of death for patients with FA, as it usually occurs earlier in life than cancer development. Despite spectacular advances in unraveling the molecular details of FA, the origin of the bone marrow failure that is central to this condition for most patients has long been puzzling and controversial. Two studies recently published in the JCI, including one in this issue, will add to the debate. They also highlight the fact that studying rare disorders can elucidate important new clinical and biological principles.
doi:10.1172/JCI45619
PMCID: PMC3007166  PMID: 21183785
17.  Dyskeratosis congenita 
FEBS letters  2010;584(17):3831-3838.
Dyskeratosis congenita (DC) was originally defined as a rare inherited bone marrow failure syndrome associated with distinct mucocutaneous features. Today DC is defined by its pathogenetic mechanism and mutations in components of the telomere maintenance machinery resulting in excessively short telomeres in highly proliferating tissues. With this new definition the disease spectrum has broadened and ranges from intrauterine growth retardation, cerebellar hypoplasia, and death in early childhood to asymptomatic mutation carriers whose descendants are predisposed to malignancy, bone marrow failure, or pulmonary disease. The degree of telomere dysfunction is the major determinant of disease onset and manifestations.
doi:10.1016/j.febslet.2010.05.019
PMCID: PMC3238451  PMID: 20493861
dyskeratosis congenita; telomerase; pulmonary fibrosis; aplastic anemia; anticipation; telomere
18.  Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference 
British Journal of Haematology  2008;142(6):859-876.
Diamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.
doi:10.1111/j.1365-2141.2008.07269.x
PMCID: PMC2654478  PMID: 18671700
Diamond Blackfan anaemia; bone marrow failure; cancer predisposition; genetics; treatment
19.  SnoRNA microarray analysis reveals changes in H/ACA and C/D RNA levels caused by dyskerin ablation in mouse liver 
The Biochemical journal  2010;429(1):33-41.
Synopsis
Small nucleolar RNAs (snoRNAs) are key components of ribonucleoprotein particles (snoRNPs) involved in modifying specific residues of ribosomal and other RNAs by pseudouridylation (H/ACA snoRNAs) or methylation (C/D snoRNAs). They are encoded within the introns of host genes, which tend to be genes whose products are involved in ribosome biogenesis or function. Though snoRNPs are abundant and ubiquitous and their components highly conserved, information concerning their expression during development or how their expression is altered in diseased states is sparse. To facilitate these studies we have developed a snoRNA microarray platform for the analysis of the abundance of snoRNAs in different RNA samples. Here we show that the microarray is sensitive and specific for the detection of snoRNAs. A mouse snoRNA microarray was used to monitor changes in abundance of snoRNAs after ablation of dyskerin, an H/ACA RNA protein component, from mouse liver, which causes a decrease in ribosome production. H/ACA snoRNAs were decreased in abundance in these livers while, unexpectedly, C/D snoRNAs were increased. The increase in C/D snoRNAs corresponded with an increase in the abundance of the mRNAs transcribed from snoRNA host genes, suggesting the increase may be part of a cellular response to defective ribosome synthesis.
doi:10.1042/BJ20091898
PMCID: PMC3105372  PMID: 20423331
H/ACA RNA; dyskerin ablation; ribosome biogenesis
20.  Anomalous electrophoretic migration of newly synthesized ribosomal RNAs and their precursors from cells with DKC1 mutations 
FEBS letters  2009;583(18):3086-3090.
Mutations in the X-linked gene, DKC1, encoding dyskerin, cause dyskeratosis congenita by leading to decreased telomerase activity and causing short telomeres. Dyskerin is also a pseudouridine synthase that modifies nascent ribosomal and other RNAs and it is not known if this function is affected by the mutations. Here we show that newly synthesized ribosomal RNA, extracted from human and mouse cells with pathogenic mutations, shows anomalous mobility in agarose gels under certain denaturation conditions. The anomalously migrating RNA is turned over rapidly. Analysis of ribosomal RNA in these cells suggests the altered mobility is due to inefficient pseudouridylation.
doi:10.1016/j.febslet.2009.08.038
PMCID: PMC2745346  PMID: 19729012
pseudouridine; ribosomal RNA; dyskerin; electrophoretic mobility; denaturing agarose gels
21.  Dyskerin Ablation in Mouse Liver Inhibits rRNA Processing and Cell Division▿ ‡  
Molecular and Cellular Biology  2009;30(2):413-422.
Dyskerin is a component of small nucleolar ribonucleoprotein complexes and acts as a pseudouridine synthase to modify newly synthesized ribosomal, spliceosomal, and possibly other RNAs. It is encoded by the DKC1 gene, the gene mutated in X-linked dyskeratosis congenita, and is also part of the telomerase complex. The yeast ortholog, Cbf5, is an essential protein, but in mammals the effect of dyskerin ablation at the cellular level is not known. Here we show that mouse hepatocytes can survive after induction of a Dkc1 deletion. In the absence of dyskerin, rRNA processing is inhibited with the accumulation of large precursors, and fibrillarin does not accumulate in nucleoli. A low rate of apoptosis is induced in the hepatocytes, which show an induction of the p53-dependent cell cycle checkpoint pathway. Signs of liver damage including an increase in serum alanine aminotransferase activity and a disordered structure at the histological and macroscopic levels are observed. In response to carbon tetrachloride administration, when wild-type hepatocytes mount a rapid proliferative response, those without dyskerin do not divide. We conclude that hepatocytes can survive without dyskerin but that the role of dyskerin in RNA modification is essential for cellular proliferation.
doi:10.1128/MCB.01128-09
PMCID: PMC2798470  PMID: 19917719
22.  Variable expression of DKC1 mutations in mice 
Genesis (New York, N.Y. : 2000)  2009;47(6):366-373.
In humans mutations in DKC1, cause the rare bone marrow failure syndrome dyskeratosis congenita. We have used gene targeting to produce mouse ES cells with Dkc1 mutations that cause DC when in humans. The mutation A353V, the most common human mutation, causes typical DC to very severe DC in humans. Male chimeric mice carrying this mutation do not pass the mutated allele to their offspring. The mutation G402E accounts for a single typical case of DC in a human family. The allele carrying this mutation was transmitted to the offspring with high efficiency. Expression of RNA and protein was reduced compared to wild type animals but no abnormalities of growth and development or in blood values were found in mutant mice. Thus Dkc1 mutations have variable expression in mice, as in humans.
doi:10.1002/dvg.20509
PMCID: PMC2704246  PMID: 19391112
23.  TINF2 Mutations in Children With Severe Aplastic Anemia 
Pediatric blood & cancer  2009;52(5):687.
doi:10.1002/pbc.21903
PMCID: PMC2860792  PMID: 19090550
24.  Diagnosing and Treating Diamond Blackfan Anemia: Results of an International Clinical Consensus Conference 
British journal of haematology  2008;142(6):859-876.
Summary
Diamond Blackfan anemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA presents during the first year of life, affecting about 7 per million live births. However, as genes mutated in DBA have been discovered, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.
doi:10.1111/j.1365-2141.2008.07269.x
PMCID: PMC2654478  PMID: 18671700
Diamond Blackfan anemia (DBA); bone marrow failure; cancer predisposition; genetics; treatment
25.  Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p– syndrome 
Aging Cell  2007;6(5):689-697.
Telomerase, which maintains the ends of chromosomes, consists of two core components, the telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC). Haploinsufficiency for TERC or TERT leads to progressive telomere shortening and autosomal dominant dyskeratosis congenita (DC). The clinical manifestations of autosomal dominant DC are thought to occur when telomeres become critically short, but the rate of telomere shortening in this condition is unknown. Here, we investigated the consequences of de novo TERT gene deletions in a large cohort of individuals with 5p– syndrome. The study group included 41 individuals in which the chromosome deletion resulted in loss of one copy of the TERT gene at 5p15.33. Telomere length in peripheral blood cells from these individuals, although within the normal range, was on average shorter than in normal controls. The shortening was more significant in older individuals suggesting an accelerated age-dependent shortening. In contrast, individuals with autosomal dominant DC due to an inherited TERC gene deletion had very short telomeres, and the telomeres were equally short regardless of the age. Although some individuals with 5p– syndrome showed clinical features that were reminiscent of autosomal dominant DC, these features did not correlate with telomere length, suggesting that these were not caused by critically short telomeres. We conclude that a TERT gene deletion leads to slightly shorter telomeres within one generation. However, our results suggest that several generations of TERT haploinsufficiency are needed to produce the very short telomeres seen in patients with DC.
doi:10.1111/j.1474-9726.2007.00324.x
PMCID: PMC2583393  PMID: 17875000
5p– syndrome; dyskeratosis congenita; haploinsufficiency; telomerase reverse transcriptase; telomerase RNA component; telomere

Results 1-25 (27)