Your browser doesn't support javascript.
loading
Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.
Henslee, Gabrielle; Williams, Christopher L; Liu, Pengfei; Bertuch, Alison A.
Afiliação
  • Henslee G; Baylor College of Medicine, Integrated Molecular and Biomedical Sciences Graduate Program, Houston, Texas 77030, USA.
  • Williams CL; Baylor College of Medicine, Department of Pediatrics, Hematology/Oncology, Houston, Texas 77030, USA.
  • Liu P; Texas Children's Hospital, Cancer and Hematology Centers, Houston, Texas 77030, USA.
  • Bertuch AA; Baylor College of Medicine, Department of Pediatrics, Hematology/Oncology, Houston, Texas 77030, USA.
Artigo em Inglês | MEDLINE | ID: mdl-33446513
ABSTRACT
Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing ACD arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.(Asp207Thrfs*22), or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo diagnóstico Idioma: Inglês Ano de publicação: 2021 Tipo de documento: Artigo País de afiliação: Estados Unidos

Similares

MEDLINE

...
LILACS

LIS

Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo diagnóstico Idioma: Inglês Ano de publicação: 2021 Tipo de documento: Artigo País de afiliação: Estados Unidos