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J Med Genet. 2015 Nov;52(11):738-48. doi: 10.1136/jmedgenet-2015-103292. Epub 2015 Sep 4.

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

Author information

1
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.
2
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
3
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
4
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.
5
Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
6
Department of Medical Genetics, University of Siena, Siena, Italy.
7
Genetica Medica, Azienda Ospedaliera Universitaria, Senese, Siena, Italy.
8
Neuropsichiatria Infantile, Azienda Ospedaliera, Universitaria Senese, Siena, Italy.
9
Department of Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
10
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
11
Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
12
Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
13
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.
14
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
15
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.
16
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.

Abstract

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.

KEYWORDS:

Copy-number; Genetics; Haematology (incl Blood transfusion); Molecular genetics; Neurology

PMID:
26342108
DOI:
10.1136/jmedgenet-2015-103292
[Indexed for MEDLINE]

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