Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita

Vulliamy, Tom; Beswick, Richard; Kirwan, Michael; Marrone, Anna; Digweed, Martin; Walne, Amanda J.; Dokal, Inderjeet

doi:10.1073/pnas.0800042105

Cited by 288 publications

(188 citation statements)

References 41 publications

(57 reference statements)

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“…Multiple modes of inheritance are associated with DC (Walne et al 2007(Walne et al , 2013aVulliamy et al 2008;Keller et al 2012;Nelson and Bertuch 2012;Le Guen et al 2013). X-linked recessive (XLR) DC is caused by DKC1 (MIM 300126) mutations.…”

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confidence: 99%

Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

et al. 2014

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Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-aminoacid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.

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Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

et al. 2014

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“…Des mutations de NOP10 [20] et NHP2 [21] sont responsables de DC par transmission autosomique récessive. Dyskérine, NOP10 et NHP2 sont associés à la fois au complexe de la télomérase et aux ribonucléo-protéines snoRNP (small nucleolar ribonucleoproteins) H/ACA qui sont des complexes nucléolaires catalysant spécifiquement la pseudo-uridylation des ARN ribosomaux.…”

Section: Formes Récessives Autosomiquesunclassified

Nouvelles formes de dyskératoses congénitales

et al. 2012

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> Les télomères sont des structures nucléopro-téiques finement régulées qui constituent les extrémités des chromosomes linéaires. Chez l'homme, les défauts de maintenance télomé-rique sont responsables de la dyskératose congé-nitale (DC), une maladie génétique rare caracté-risée par une aplasie médullaire, un vieillissement prématuré et une prédisposition aux cancers. Des données récentes qui proviennent d'une étude de patients atteints du syndrome de HoyeraalHreidarsson (syndrome HH), variant sévère de DC, ont mis en évidence la grande hétérogénéité moléculaire de cette maladie, dont certaines formes sont liées à des défauts de facteurs impliqués, non pas dans la régulation de la taille des télomères, mais dans leur protection et leur réplication. < de TERT est finement régulée et principalement limitée aux cellules germinales, aux cellules souches hématopoïétiques ainsi qu'à certaines cellules activées (comme les lymphocytes) [2]. La plupart des cellules somatiques, comme les fibroblastes, n'expriment pas ou peu la molécule TERT et, par conséquent, ont une capacité proliférative limitée [3]. La télomérase agit sous forme d'un complexe moléculaire composé de nombreux autres facteurs dont la dyskérine, la matrice d'ARN TERC (telomerase RNA component) et les cofacteurs NOP10 (nucleolar protein 10), NHP2 (non-histone chromosome protein 2), TCAB1 (telomerase Cajal body protein 1) et GAR1. Le rôle du raccourcissement télomérique dans l'induction de la sénescence et la limitation de la prolifération cellulaire a été clairement démontré. En effet, l'immortalisation de fibroblastes primaires peut être induite par l'expression ectopique de TERT, le composant transcriptase inverse de la télomérase, permettant le maintien d'une taille stable des télomères au cours des divisions successives [4] Les télomères : des structures ribonucléoprotéiques complexes finement réguléesLes télomères constituent les extrémités des chromosomes linéaires et sont composés, chez les vertébrés, de répétitions de séquences hexamériques TTAGGG. Ils forment une structure unique qui interagit avec des facteurs dont le rôle est de protéger l'extrémité chromosomique de la dégradation et/ou de la fusion. Au cours des divisions cellulaires, les ADN polymérases conventionnelles sont incapables de répliquer totalement la fin des chromosomes, ce qui conduit à une perte progressive des séquences télomériques. Si les télomères atteignent une taille trop courte, les cellules stoppent leur prolifération et entrent dans un état de sénescence réplicative et/ou en apoptose [1]. Ce processus d'arrêt réplicatif, qui dépend de la protéine proapoptotique p53, prévient l'instabilité chromosomique et les proliférations cellulaires incontrôlées. Pour contrer le raccourcissement des télomères, la télo-mérase TERT (telomerase reverse transcriptase), une transcriptase inverse, ajoute des répétitions TTAGGG au cours de chaque division cellulaire. L'expression

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“…Homozygous mutations in the H/ACA motif binding Nhp2 and Nop10 components of telomerase have been found to be associated with AR-DC [178,179]. These two proteins are integral components of the H/ACA ribonucleoprotein complex and a loss of their function, similar to cases of X-linked DC, are associated with decreased telomerase RNA levels and compromised telomere maintenance.…”

Section: Dyskeratosis Congenitamentioning

confidence: 99%

“…These two proteins are integral components of the H/ACA ribonucleoprotein complex and a loss of their function, similar to cases of X-linked DC, are associated with decreased telomerase RNA levels and compromised telomere maintenance. Extremely rare, only three families with homozygous mutations in either Nhp2 or Nop10 have been identified [178,179].…”

Section: Dyskeratosis Congenitamentioning

confidence: 99%

Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

Trudeau¹,

Wong²

2010

CPPM

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Premature loss of telomere repeats underlies the pathologies of inherited bone marrow failure syndromes. Over the past decade, researchers have mapped genetic lesions responsible for the accelerated loss of telomere repeats. Haploinsufficiencies in the catalytic core components of the telomere maintenance enzyme telomerase, as well as genetic defects in telomerase holoenzyme components responsible for enzyme stability, have been linked to hematopoietic failure pathologies. Frequencies of these disease-associated alleles in human populations are low. Accordingly, the diseases themselves are rare. On the other hand, single nucleotide polymorphisms of telomerase enzyme components are found with much higher frequencies, with several non-synonymous SNP alleles observed in 2-4% of the general population. Importantly, recent advents of molecular diagnostic techniques have uncovered links between telomere length maintenance deficiencies and an increasing number of pathologies unrelated to the hematopoietic system. In these cases, short telomere length correlates to tissue renewal capacities and predicts clinical progression and disease severity. To the authors of this review, these new discoveries imply that even minor genetic defects in telomere maintenance can culminate in the premature failure of tissue compartments with high renewal rates. In this review, we discuss the biology and molecules of telomere maintenance, and the pathologies associated with an accelerated loss of telomeres, along with their etiologies. We also discuss single nucleotide polymorphisms of key telomerase components and their association with tissue renewal deficiency syndromes and other pathologies. We suggest that inter-individual variability in telomere maintenance capacity could play a significant role in chronic inflammatory diseases, and that this is not yet fully appreciated in the translational research of pharmacogenomics and personalized medicine.

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Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita

Cited by 288 publications

References 41 publications

Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

Nouvelles formes de dyskératoses congénitales

Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

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