The inherited disorder dyskeratosis congenita is characterized by short telomeres, mucocutaneous abnormalities, and bone marrow failure. The underlying genetic mutations are known in ~40% of cases and are found within genes associated with telomere maintenance and function. In this episode, Tom Vulliamy and Hemanth Tummala discuss their work, which identifies biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in three families with severe dyskeratosis congenita. These mutations inhibit the deadenylation activity of PARN, resulting in the downregulation of 4 genes involved in telomere maintenance and shortened telomeres. The results of this study establish a causative role for PARN in a severe form of dyskeratosis congenita.
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
Hemanth Tummala, Amanda Walne, Laura Collopy, Shirleny Cardoso, Josu de la Fuente, Sarah Lawson, James Powell, Nicola Cooper, Alison Foster, Shehla Mohammed, Vincent Plagnol, Thomas Vulliamy, Inderjeet Dokal