title: Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.
abstract: Dyskeratosis congenita (DC) and related syndromes are inherited, life-threatening bone marrow (BM) failure disorders, and approximately 40% of cases are currently uncharacterized at the genetic level. Here, using whole exome sequencing (WES), we have identified biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in 3 families with individuals exhibiting severe DC. PARN is an extensively characterized exonuclease with deadenylation activity that controls mRNA stability in part and therefore regulates expression of a large number of genes. The DC-associated mutations identified affect key domains within the protein, and evaluation of patient cells revealed reduced deadenylation activity. This deadenylation deficiency caused an early DNA damage response in terms of nuclear p53 regulation, cell-cycle arrest, and reduced cell viability upon UV treatment. Individuals with biallelic PARN mutations and PARN-depleted cells exhibited reduced RNA levels for several key genes that are associated with telomere biology, specifically TERC, DKC1, RTEL1, and TERF1. Moreover, PARN-deficient cells also possessed critically short telomeres. Collectively, these results identify a role for PARN in telomere maintenance and demonstrate that it is a disease-causing gene in a subset of patients with severe DC.
authors.forename: Hemanth
authors.initials: H
authors.lastname: Tummala
authors.forename: Amanda
authors.initials: A
authors.lastname: Walne
authors.forename: Laura
authors.initials: L
authors.lastname: Collopy
authors.forename: Shirleny
authors.initials: S
authors.lastname: Cardoso
authors.forename: Josu
authors.initials: J
authors.lastname: de la Fuente
authors.forename: Sarah
authors.initials: S
authors.lastname: Lawson
authors.forename: James
authors.initials: J
authors.lastname: Powell
authors.forename: Nicola
authors.initials: N
authors.lastname: Cooper
authors.forename: Alison
authors.initials: A
authors.lastname: Foster
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Thomas
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000483:Alleles; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004249:DNA Damage; D015536:Down-Regulation; D019871:Dyskeratosis Congenita / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005095:Exoribonucleases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D010154:Pakistan / Q000208:ethnology; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D017384:Sequence Deletion; D059505:Telomere Homeostasis / Q000235:genetics*
chemical_list: D005095:Exoribonucleases; D020033:Protein Isoforms; D034741:RNA, Small Interfering