TY - JOUR
T1 - Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
AU - Dhanraj, Santhosh
AU - Gunja, Sethu Madhava Rao
AU - Deveau, Adam P.
AU - Nissbeck, Mikael
AU - Boonyawat, Boonchai
AU - Coombs, Andrew J.
AU - Renieri, Alessandra
AU - Mucciolo, Mafalda
AU - Marozza, Annabella
AU - Buoni, Sabrina
AU - Turner, Lesley
AU - Li, Hongbing
AU - Jarrar, Ameer
AU - Sabanayagam, Mathura
AU - Kirby, Melanie
AU - Shago, Mary
AU - Pinto, Dalila
AU - Berman, Jason N.
AU - Scherer, Stephen W.
AU - Virtanen, Anders
AU - Dror, Yigal
PY - 2015/9/4
Y1 - 2015/9/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954387397&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2015-103292
DO - 10.1136/jmedgenet-2015-103292
M3 - Article
C2 - 26342108
AN - SCOPUS:84954387397
SN - 0022-2593
VL - 52
SP - 738
EP - 748
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 11
ER -