Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).
J Med Genet
; 52(11): 738-48, 2015 Nov.
Article
em En
| MEDLINE
| ID: mdl-26342108
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Doenças da Medula Óssea
/
Deficiências do Desenvolvimento
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Deleção de Sequência
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Mutação de Sentido Incorreto
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Exorribonucleases
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article