Megalencephalic leukoencephalopathy with subcortical cysts type 1 (MLC1) due to a homozygous deep intronic splicing mutation (c.895-226T>G) abrogated in vitro using an antisense morpholino oligonucleotide

Cecilia Mancini, Giovanna Vaula, Laura Scalzitti, Simona Cavalieri, Enrico Bertini, Chiara Aiello, Cinzia Lucchini, Richard A. Gatti, Alessandro Brussino, Alfredo Brusco

Research output: Contribution to journalArticlepeer-review

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts is an autosomal recessive disease characterized by early onset macrocephaly; developmental delay; motor disability in the form of progressive spasticity and ataxia; seizures; cognitive decline; and characteristic magnetic resonance imaging findings. Mutations in two genes, MLC1 (22q13.33; 75 % of patients) or HEPACAM (11q24; 20 % of patients), are associated with the disease. We describe an adult MLC patient with moderate clinical symptoms. MLC1 cDNA analysis from lymphoblasts showed a strong transcript reduction and identified a 246-bp pseudoexon containing a premature stop codon between exons 10 and 11, due to a homozygous c.895-226 T>G deep-intronic mutation. This category of mutations is often overlooked, being outside of canonically sequenced genomic regions. The mutation c.895-226 T>G has a leaky effect on splicing leaving part of the full-length transcript. Its role on splicing was confirmed using a minigene assay and an antisense morpholinated oligonucleotide targeted to the aberrant splice site in vitro, which partially abrogated the mutation effect.

Original languageEnglish
Pages (from-to)205-214
Number of pages10
JournalNeurogenetics
Volume13
Issue number3
DOIs
Publication statusPublished - Aug 2012

Keywords

  • AMO
  • Antisense oligonucleotide
  • Homozygosis of a splicing mutation
  • Megalencephalic leukoencephalopathy type 1
  • MLC1
  • Van der Knaap disease

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Genetics

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