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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Santhosh
S
Dhanraj
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Sethu Madhava Rao
SM
Gunja
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Adam P
AP
Deveau
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Mikael
M
Nissbeck
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Boonchai
B
Boonyawat
Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
Andrew J
AJ
Coombs
Department of Medical Genetics, University of Siena, Siena, Italy.
Alessandra
A
Renieri
Genetica Medica, Azienda Ospedaliera Universitaria, Senese, Siena, Italy.
Mafalda
M
Mucciolo
Genetica Medica, Azienda Ospedaliera Universitaria, Senese, Siena, Italy.
Annabella
A
Marozza
Neuropsichiatria Infantile, Azienda Ospedaliera, Universitaria Senese, Siena, Italy.
Sabrina
S
Buoni
Department of Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Lesley
L
Turner
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Hongbing
H
Li
Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
Ameer
A
Jarrar
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Mathura
M
Sabanayagam
Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Melanie
M
Kirby
Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
Mary
M
Shago
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, The Mindich Child Health & Development Institute, Mount Sinai School of Medicine, New York, New York, USA.
Dalila
D
Pinto
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
Jason N
JN
Berman
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Stephen W
SW
Scherer
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Anders
A
Virtanen
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Yigal
Y
Dror
D000483:Alleles; D000818:Animals; D001855:Bone Marrow Diseases / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism; D005095:Exoribonucleases / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009186:Myelin Sheath / Q000235:genetics / Q000473:pathology; D017384:Sequence Deletion; D059505:Telomere Homeostasis / Q000235:genetics; D055815:Young Adult; D015027:Zebrafish
D005095:Exoribonucleases
Copy-number; Genetics; Haematology (incl Blood transfusion); Molecular genetics; Neurology