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.

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

MANCINI, CECILIA;CAVALIERI, Simona;BRUSSINO, Alessandro;BRUSCO, Alfredo
2012-01-01

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.
2012
13
205
214
http://link.springer.com/article/10.1007%2Fs10048-012-0331-z
MLC1; Megalencephalic leukoencephalopathy type 1; Van der Knapp disease; Homozygosis of a splicing mutation; Antisense oligonucleotide; AMO
Cecilia Mancini;Giovanna Vaula;Laura Scalzitti;Simona Cavalieri;Enrico Bertini;Chiara Aiello;Cinzia Lucchini;Richard A. Gatti;Alessandro Brussino;Alfredo Brusco
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/71172
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