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

Dhanraj, S., Gunja, S.M., Deveau, A.P., Nissbeck, M., Boonyawat, B., Coombs, A.J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., Jarrar, A., Sabanayagam, M., Kirby, M., Shago, M., Pinto, D., Berman, J.N., Scherer, S.W., Virtanen, A., Dror, Y.
Journal of Medical Genetics   52(11): 738-48 (Journal)
Registered Authors
Berman, Jason, Coombs, Andrew, Deveau, Adam, Jarrar, Ameer
Copy-number, Genetics, Haematology (incl Blood transfusion), Molecular genetics, Neurology
MeSH Terms
  • Alleles
  • Animals
  • Bone Marrow Diseases/genetics*
  • Bone Marrow Diseases/metabolism
  • Child
  • DNA Mutational Analysis
  • Developmental Disabilities/genetics*
  • Developmental Disabilities/metabolism
  • Exoribonucleases/genetics*
  • Female
  • Genetic Testing
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Myelin Sheath/genetics
  • Myelin Sheath/pathology
  • Sequence Deletion*
  • Telomere Homeostasis/genetics
  • Young Adult
  • Zebrafish
26342108 Full text @ J. Med. Genet.
Deadenylation 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.
We 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.
We 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.
Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes