RESUMEN
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.
RESUMEN
Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole-blood transcriptomic profiling in a subset of patients with inherited bone marrow failure (IBMF) whose diseases are clinically and genetically characterized as Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), and dyskeratosis congenita (DC). We hypothesized that annotating whole-blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood-derived transcriptomes revealed significant skewing toward upregulated genes in patients with FA when compared with controls. Patients with SDS or DC also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense-mediated decay), and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cutoff (false discovery rate < 0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterized patients with BMF revealed a striking overlap of genes, including 22 from the discovery set, which indicates a unified transcriptional drive across the classic (FA, SDS, and DC) and uncharacterized BMF subtypes. This study has relevance in disease pathogenesis, for example, in explaining the features (including the BMF) common to all patients with IBMF and suggests harnessing this transcriptional signature for patient benefit.
Asunto(s)
Enfermedades de la Médula Ósea , Disqueratosis Congénita , Anemia de Fanconi , Enfermedades de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea , Anemia de Fanconi/genética , Perfilación de la Expresión Génica , HumanosRESUMEN
Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.
Asunto(s)
Trastornos de Fallo de la Médula Ósea/diagnóstico , Disqueratosis Congénita/diagnóstico , Retardo del Crecimiento Fetal/diagnóstico , Tamización de Portadores Genéticos/métodos , Discapacidad Intelectual/diagnóstico , Microcefalia/diagnóstico , Telómero/patología , Adolescente , Adulto , Factores de Edad , Anciano , Enfermedades Asintomáticas , Trastornos de Fallo de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea/patología , Estudios de Casos y Controles , Niño , Preescolar , Disqueratosis Congénita/genética , Disqueratosis Congénita/patología , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/patología , Heterocigoto , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Microcefalia/genética , Microcefalia/patología , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Telómero/metabolismo , Homeostasis del TelómeroRESUMEN
Inherited bone marrow failure (BMF) syndromes are a heterogeneous group of diseases characterized by defective hematopoiesis and often predisposing to myelodysplastic syndrome (MDS) and acute myelogenous leukemia. We have studied a large family consisting of several affected individuals with hematologic abnormalities, including one family member who died of acute leukemia. By whole-exome sequencing, we identified a novel frameshift variant in the ubiquitously expressed transcription factor specificity protein 1 (SP1). This heterozygous variant (c.1995delA) truncates the canonical Sp1 molecule in the highly conserved C-terminal DNA-binding zinc finger domains. Transcriptomic analysis and gene promoter characterization in patients' blood revealed a hypermorphic effect of this Sp1 variant, triggering superactivation of Sp1-mediated transcription and driving significant up-regulation of Sp1 target genes. This familial genetic study indicates a central role for Sp1 in causing autosomal dominant transmission of BMF, thereby confirming its critical role in hematopoiesis in humans.
Asunto(s)
Trastornos de Fallo de la Médula Ósea/genética , Mutación del Sistema de Lectura/genética , Factor de Transcripción Sp1/genética , Transcripción Genética/genética , Femenino , Humanos , Masculino , Linaje , Transcriptoma/genética , Regulación hacia Arriba/genética , Dedos de Zinc/genéticaAsunto(s)
Aminopeptidasas/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Disqueratosis Congénita/genética , Mutación Puntual , Serina Proteasas/genética , Complejo Shelterina , Proteínas de Unión a Telómeros , Adulto , Aminopeptidasas/química , Niño , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/química , Femenino , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Mutación Missense , Linaje , Fenotipo , Conformación Proteica , Serina Proteasas/química , Complejo Shelterina/genética , Acortamiento del Telómero , Proteínas de Unión a Telómeros/genéticaRESUMEN
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.
Asunto(s)
Disqueratosis Congénita/diagnóstico , Disqueratosis Congénita/genética , Exoma/genética , Variación Genética/genética , ADN Ligasa (ATP)/genética , Proteínas de Unión al ADN/genética , Humanos , Linaje , Hidrolasas Diéster Fosfóricas/genética , Análisis de Secuencia de ADN , Síndrome , Factores de Transcripción/genéticaRESUMEN
A substantial number of individuals with bone marrow failure (BMF) present with one or more extra-hematopoietic abnormality. This suggests a constitutional or inherited basis, and yet many of them do not fit the diagnostic criteria of the known BMF syndromes. Through exome sequencing, we have now identified a subgroup of these individuals, defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21). They present with global BMF, and one individual developed a hematological cancer (acute myeloid leukemia) in childhood. We show that the encoded protein associates with rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid cells obtained from an affected individual exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced amounts of rRNA. Characterization of mutations revealed impairment in interactions with cofactors (PA2G4, HSPA8, and ZNF622) involved in 60S maturation. DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death. Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.
Asunto(s)
Anemia Aplásica/complicaciones , Anemia Aplásica/genética , Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/genética , Proteínas del Choque Térmico HSP40/genética , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/genética , Mutación/genética , Neoplasias/complicaciones , Neoplasias/genética , Subunidades Ribosómicas Grandes de Eucariotas/metabolismo , Subunidades Ribosómicas Grandes de Eucariotas/patología , Secuencia de Aminoácidos , Trastornos de Fallo de la Médula Ósea , Proliferación Celular , Forma de la Célula , Niño , Preescolar , Femenino , Proteínas del Choque Térmico HSP40/química , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/genética , Masculino , Unión Proteica , ARN Ribosómico/biosíntesisRESUMEN
Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.
Asunto(s)
Disqueratosis Congénita/genética , Epigénesis Genética , Telomerasa/genética , Alelos , Secuencia de Bases , Células Cultivadas , Estudios de Cohortes , Familia , Humanos , Patrón de Herencia , Datos de Secuencia Molecular , Mutación , Linaje , ARN/genéticaAsunto(s)
Anemia Aplásica/complicaciones , Anemia Aplásica/genética , Variación Genética , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/genética , Recombinasas/genética , Anemia Aplásica/diagnóstico , Enfermedades de la Médula Ósea , Trastornos de Fallo de la Médula Ósea , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Hemoglobinuria Paroxística/diagnóstico , Humanos , Análisis de Secuencia de ADNRESUMEN
Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.
Asunto(s)
ADN Helicasas/genética , Reparación del ADN/genética , Hemoglobinuria Paroxística/genética , Mitocondrias/genética , Acetilcisteína/metabolismo , Anemia Aplásica , Enfermedades de la Médula Ósea , Trastornos de Fallo de la Médula Ósea , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Mitocondrias/efectos de los fármacos , Mitomicina/toxicidad , Mutación , Linaje , Fosforilación , Especies Reactivas de Oxígeno , Sesquiterpenos/toxicidadRESUMEN
Dyskeratosis congenita (DC) and its phenotypically severe variant, Hoyeraal-Hreidarsson syndrome (HHS), are multisystem bone-marrow-failure syndromes in which the principal pathology is defective telomere maintenance. The genetic basis of many cases of DC and HHS remains unknown. Using whole-exome sequencing, we identified biallelic mutations in RTEL1, encoding a helicase essential for telomere maintenance and regulation of homologous recombination, in an individual with familial HHS. Additional screening of RTEL1 identified biallelic mutations in 6/23 index cases with HHS but none in 102 DC or DC-like cases. All 11 mutations in ten HHS individuals from seven families segregated in an autosomal-recessive manner, and telomere lengths were significantly shorter in cases than in controls (p = 0.0003). This group had significantly higher levels of telomeric circles, produced as a consequence of incorrect processing of telomere ends, than did controls (p = 0.0148). These biallelic RTEL1 mutations are responsible for a major subgroup (â¼29%) of HHS. Our studies show that cells harboring these mutations have significant defects in telomere maintenance, but not in homologous recombination, and that incorrect resolution of T-loops is a mechanism for telomere shortening and disease causation in humans. They also demonstrate the severe multisystem consequences of its dysfunction.
Asunto(s)
ADN Helicasas/genética , Disqueratosis Congénita/genética , Retardo del Crecimiento Fetal/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Mutación , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Exoma , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Datos de Secuencia Molecular , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de Proteína/métodos , Telómero/genética , Acortamiento del Telómero/genéticaRESUMEN
Dyskeratosis congenita and its variants have overlapping phenotypes with many disorders including Coats plus, and their underlying pathology is thought to be one of defective telomere maintenance. Recently, biallelic CTC1 mutations have been described in patients with syndromes overlapping Coats plus. CTC1, STN1 and TEN1 are part of the telomere-capping complex involved in maintaining telomeric structural integrity. Based on phenotypic overlap we screened 73 genetically uncharacterized patients with dyskeratosis congenita and related bone marrow failure syndromes for mutations in this complex. Biallelic CTC1 mutations were identified in 6 patients but none in either STN1 or TEN1. We have expanded the phenotypic spectrum associated with CTC1 mutations and report that intracranial and retinal abnormalities are not a defining feature, as well as showing that the effect of these mutations on telomere length is variable. The study also demonstrates the lack of disease-causing mutations in other components of the telomere-capping complex.
Asunto(s)
Disqueratosis Congénita/genética , Hemoglobinuria Paroxística/genética , Mutación , Proteínas de Unión a Telómeros/genética , Anemia Aplásica , Enfermedades de la Médula Ósea , Trastornos de Fallo de la Médula Ósea , Disqueratosis Congénita/diagnóstico , Femenino , Hemoglobinuria Paroxística/diagnóstico , Heterocigoto , Humanos , Masculino , Linaje , Sistema de Registros , Telómero/metabolismo , Acortamiento del TelómeroRESUMEN
Aplastic anemia (AA) and myelodysplasia (MDS) are forms of bone marrow failure that are often part of the same progressive underlying disorder. While most cases are simplex and idiopathic, some show a clear pattern of inheritance; therefore, elucidating the underlying genetic cause could lead to a greater understanding of this spectrum of disorders. We used a combination of exome sequencing and SNP haplotype analysis to identify causative mutations in a family with a history of autosomal-dominant AA/MDS. We identified a heterozygous mutation in SRP72, a component of the signal recognition particle (SRP) that is responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum. A subsequent screen revealed another autosomal-dominant family with an inherited heterozygous SRP72 mutation. Transfection of these sequences into mammalian cells suggested that these proteins localize incorrectly within the cell. Furthermore, coimmunoprecipitation of epitope-tagged SRP72 indicated that the essential RNA component of the SRP did not fully associate with one of the SRP72 variants. These results suggest that inherited mutations in a component of the SRP have a role in the pathophysiology of AA/MDS, identifying a third pathway for developing these disorders alongside transcription factor and telomerase mutations.
Asunto(s)
Anemia Aplásica/genética , Exoma , Mutación , Síndromes Mielodisplásicos/genética , Partícula de Reconocimiento de Señal/genética , Anemia Aplásica/fisiopatología , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Biblioteca de Genes , Heterocigoto , Humanos , Masculino , Síndromes Mielodisplásicos/fisiopatología , Linaje , ARN/genética , Partícula de Reconocimiento de Señal/metabolismo , Telomerasa/genética , Telomerasa/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis.
Asunto(s)
Anemia Aplásica/genética , Receptores de Trombopoyetina/genética , Preescolar , Consanguinidad , Exoma , Familia , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Linaje , Análisis de Secuencia de ADN , TelómeroRESUMEN
Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure disorder with known mutations in components of telomerase and telomere shelterin. Recent work in a mouse model with a dyskerin mutation has implicated an increased DNA damage response as part of the cellular pathology, while mouse models with Terc and Tert mutations displayed a normal response. To clarify how these contradictory results might apply to DC pathology in humans, we studied the cellular phenotype in primary cells from DC patients of several genetic subtypes, focussing on T lymphocytes to remain close to the haematopoietic system. We observed novel cell cycle abnormalities in conjunction with impaired growth and an increase in apoptosis. Using flow cytometry and confocal microscopy we examined induction of the DNA damage proteins γ-H2AX and 53BP1 and the cell cycle protein TP53 (p53). We found an increase in damage foci at telomeres in lymphocytes and an increase in the basal level of DNA damage in fibroblasts, but crucially no increased response to DNA damaging agents in either cell type. As the response to induced DNA damage was normal and levels of global DNA damage were inconsistent between cell types, DNA damage may contribute differently to the pathology in different tissues.
Asunto(s)
Daño del ADN , Disqueratosis Congénita/genética , Adolescente , Adulto , Apoptosis/genética , Ciclo Celular/genética , Preescolar , Disqueratosis Congénita/inmunología , Disqueratosis Congénita/metabolismo , Femenino , Fibroblastos/metabolismo , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Microscopía Confocal , Linfocitos T/metabolismo , Linfocitos T/patología , Telómero/genética , Técnicas de Cultivo de Tejidos , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53 , Regulación hacia Arriba/genética , Adulto JovenRESUMEN
Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund-Thomson syndrome (RTS-a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.
Asunto(s)
Disqueratosis Congénita/genética , Neutropenia/genética , Proteínas Nucleares/genética , Trastornos de la Pigmentación/genética , Síndrome Rothmund-Thomson/genética , Telómero/genética , Estudios de Casos y Controles , Consanguinidad , Análisis Mutacional de ADN , Femenino , Proteínas Activadoras de GTPasa , Ligamiento Genético , Homocigoto , Humanos , Masculino , Mutación , Polimorfismo de Nucleótido Simple , Telómero/metabolismoRESUMEN
The primary pathology in many cases of myelodysplasia (MDS) and acute myeloid leukemia (AML) remains unknown. In some cases, two or more affected members have been identified in the same family. To date, mutations in two genes have been directly implicated: the hematopoietic transcription factors RUNX1 (runt-related transcription factor 1) and CEBPA (CCATT-box enhancer binding protein alpha). However, there are also other familial cases of MDS/AML where the genetic basis remains unknown. Both MDS, and to a lesser extent AML, have been observed in cases of the bone marrow failure syndrome dyskeratosis congenita, in which telomerase mutations have been identified. Recently, an increased incidence of telomerase reverse transcriptase mutations has been reported in a series of de novo AML. We have now identified novel mutations in the telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT) within 4 of 20 families presenting with familial MDS/AML. Functional analysis has demonstrated that all mutations adversely impact on telomerase activity in vitro, and affected individuals have short telomeres. These families, in conjunction with a review of previously published cases, help to further define the pathological role of telomerase mutations in MDS/AML and have implications for the biology, treatment and screening regimen of de novo cases.
Asunto(s)
Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , ARN/genética , Telomerasa/genética , Secuencia de Aminoácidos , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , LinajeRESUMEN
Dyskeratosis congenita (DC) is a rare inherited syndrome exhibiting marked clinical and genetic heterogeneity. It is characterised by mucocutaneous abnormalities, bone marrow failure and a predisposition to cancer. Bone marrow failure is the principal cause of premature mortality. Studies over the last 10 years have demonstrated that DC is principally a disease of defective telomere maintenance. All DC patients have very short telomeres and the genetically characterised cases of DC have mutations in six genes which either encode components of the telomerase complex (DKC1, TERC, TERT, NOP10, NHP2) or shelterin (TINF2); these are important in the elongation and protection of the telomeric end, respectively. These advances have led to the recognition of cryptic forms of DC, such as presentations with aplastic anaemia and myelodysplasia. They have also increased our understanding of normal haematopoiesis and provided new insights to the aetiology of some cases of aplastic anaemia and related haematological disorders.