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1.
Hum Mol Genet ; 29(6): 907-922, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31985013

RESUMO

Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.


Assuntos
Disceratose Congênita/patologia , Retardo do Crescimento Fetal/patologia , Deficiência Intelectual/patologia , Microcefalia/patologia , Mutação , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fibrose Pulmonar/patologia , RNA Ribossômico/biossíntese , Ribonucleoproteínas Nucleares Pequenas/deficiência , Ribonucleoproteínas Nucleares Pequenas/genética , Idoso , Sequência de Aminoácidos , Disceratose Congênita/etiologia , Feminino , Retardo do Crescimento Fetal/etiologia , Humanos , Recém-Nascido , Deficiência Intelectual/etiologia , Masculino , Microcefalia/etiologia , Pessoa de Meia-Idade , Proteínas Nucleares/química , Linhagem , Regiões Promotoras Genéticas , Fibrose Pulmonar/etiologia , Ribonucleoproteínas Nucleares Pequenas/química , Homologia de Sequência , Telomerase/genética , Transcrição Gênica
2.
EMBO Mol Med ; 11(7): e10201, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31273937

RESUMO

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.


Assuntos
Disceratose Congênita/metabolismo , Exorribonucleases/deficiência , Retardo do Crescimento Fetal/metabolismo , Deficiência Intelectual/metabolismo , Microcefalia/metabolismo , RNA Ribossômico/biossíntese , Homeostase do Telômero , Telômero/metabolismo , Animais , Pré-Escolar , Modelos Animais de Doenças , Disceratose Congênita/genética , Disceratose Congênita/patologia , Exorribonucleases/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Camundongos , Camundongos Knockout , Microcefalia/genética , Microcefalia/patologia , RNA Ribossômico/genética , Complexo Shelterina , Telômero/genética , Telômero/patologia , Proteínas de Ligação a Telômeros
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