Document Detail

In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2.
MedLine Citation:
PMID:  23188051     Owner:  NLM     Status:  MEDLINE    
Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder affecting about 1:33 000 newborns, mainly characterized by the development of tumors of the nervous system and ocular abnormalities. Around 85% of germline NF2 mutations are point mutations. Among them, ∼25% affect splicing and are associated with a variable disease severity. In the context of our NF2 Multidisciplinary Clinics, we have identified a patient fulfilling clinical criteria for the disease and exhibiting a severe phenotype. The patient carries a deep intronic mutation (g. 74409T>A, NG_009057.1) that produces the insertion of a cryptic exon of 167pb in the mature mRNA between exons 13 and 14, resulting in a truncated merlin protein (p.Pro482Profs*39). A mutation-specific antisense phosphorodiamidate morpholino oligomer was designed and used in vitro to effectively restore normal NF2 splicing in patient-derived primary fibroblasts. In addition, merlin protein levels were greatly recovered after morpholino treatment, decreasing patient's fibroblasts in vitro proliferation capacity and restoring cytoeskeleton organization. To our knowledge, this is the first NF2 case caused by a deep intronic mutation in which an in vitro antisense therapeutic approximation has been tested. These results open the possibility of using this approach in vivo for this type of mutation causing NF2.
Elisabeth Castellanos; Imma Rosas; Ares Solanes; Isabel Bielsa; Conxi Lázaro; Cristina Carrato; Cristina Hostalot; Pepe Prades; Francesc Roca-Ribas; Ignacio Blanco; Eduard Serra;
Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-28
Journal Detail:
Title:  European journal of human genetics : EJHG     Volume:  21     ISSN:  1476-5438     ISO Abbreviation:  Eur. J. Hum. Genet.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2013-11-04     Revised Date:  2014-07-17    
Medline Journal Info:
Nlm Unique ID:  9302235     Medline TA:  Eur J Hum Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  769-73     Citation Subset:  IM    
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MeSH Terms
Cells, Cultured
Fibroblasts / cytology,  drug effects
Germ-Line Mutation / genetics
Introns / genetics
Morpholinos / administration & dosage*,  genetics,  therapeutic use
Neurofibromatosis 2 / genetics*,  pathology,  therapy*
Neurofibromin 2 / genetics*
RNA, Antisense / genetics
Reg. No./Substance:
0/Morpholinos; 0/Neurofibromin 2; 0/RNA, Antisense
Comment In:
Eur J Hum Genet. 2013 Jul;21(7):701-2   [PMID:  23188050 ]
Erratum In:
Eur J Hum Genet. 2014 Jan;22(1):153

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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