Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)

• Published in: Journal of medical genetics Vol. 52; no. 11; pp. 738 - 748
• Main Authors: Dhanraj, Santhosh, Gunja, Sethu Madhava Rao, Deveau, Adam P, Nissbeck, Mikael, Boonyawat, Boonchai, Coombs, Andrew J, Renieri, Alessandra, Mucciolo, Mafalda, Marozza, Annabella, Buoni, Sabrina, Turner, Lesley, Li, Hongbing, Jarrar, Ameer, Sabanayagam, Mathura, Kirby, Melanie, Shago, Mary, Pinto, Dalila, Berman, Jason N, Scherer, Stephen W, Virtanen, Anders, Dror, Yigal
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.11.2015
• Subjects: Alleles; Anemia; Animals; Biosynthesis; Bone marrow; Bone Marrow Diseases - genetics; Bone Marrow Diseases - metabolism; Child; Child development; Copy-number; Deformities; Developmental Disabilities - genetics; Developmental Disabilities - metabolism; DNA Mutational Analysis; Exoribonucleases - genetics; Female; Fibroblasts; Genes; Genetic Testing; Genetics; Genomes; Genomics; Haematology (incl Blood transfusion); Humans; Infant; Male; Mental disorders; Middle Aged; Molecular genetics; Mutation; Mutation, Missense; Myelin Sheath - genetics; Myelin Sheath - pathology; Neurology; Patients; Ribonucleic acid; RNA; Sequence Deletion; Skin; Telomere Homeostasis - genetics; Young Adult; Zebrafish; United States > US; Neurology; Genetics; Haematology (incl Blood transfusion); Copy-number; Molecular genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2015-103292

BackgroundDeadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN.MethodsWe identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease.ResultsWe identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease.ConclusionsLarge monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.