Sep 6, 2015

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

Journal of Medical Genetics
Santhosh DhanrajYigal Dror

Abstract

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 ...Continue Reading

Mentioned in this Paper

Bone Marrow Failure Syndromes
Neurologic Manifestations
Germ-Line Mutation
Telomere Lengthening
Gene Knockdown Techniques
Genome
RNA, Untranslated
Genetic Screening Method
PARN protein, human
Bone Marrow

Related Feeds

Auditory Perception

Auditory perception is the ability to receive and interpret information attained by the ears. Here is the latest research on factors and underlying mechanisms that influence auditory perception.