uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Inst Med Sci, Toronto, ON, Canada..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Show others and affiliations
2015 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, no 11, 738-748 p.Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 52, no 11, 738-748 p.
Keyword [en]
Genetics, Haematology (incl Blood transfusion), Copy-number, Molecular genetics, Neurology
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-269251DOI: 10.1136/jmedgenet-2015-103292ISI: 000364633100003PubMedID: 26342108OAI: oai:DiVA.org:uu-269251DiVA: diva2:884965
Funder
Swedish Research Council
Available from: 2015-12-17 Created: 2015-12-15 Last updated: 2017-12-01Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Gunja, Sethu Madhava RaoNissbeck, MikaelVirtanen, Anders

Search in DiVA

By author/editor
Gunja, Sethu Madhava RaoNissbeck, MikaelVirtanen, Anders
By organisation
Chemical Biology
In the same journal
Journal of Medical Genetics
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 775 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf