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Whole‐Exome Sequencing Identifies a Variant of the Mitochondrial MT ‐ ND 1 Gene Associated with Epileptic Encephalopathy: W est Syndrome Evolving to L ennox– G astaut Syndrome
Author(s) -
Delmiro Aitor,
Rivera Henry,
GarcíaSilva María Teresa,
GarcíaConsuegra Inés,
MartínHernández Elena,
QuijadaFraile Pilar,
Las Heras Rogelio Simón,
MorenoIzquierdo Ana,
Martín Miguel Ángel,
Arenas Joaquín,
MartínezAzorín Francisco
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22445
Subject(s) - biology , exome sequencing , lennox–gastaut syndrome , west syndrome , exome , mitochondrial dna , epilepsy , gene , genetics , encephalopathy , mutation , neuroscience , medicine
We describe a W est syndrome ( WS ) patient with unidentified etiology that evolved to L ennox– G astaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole‐exome sequencing ( WES ) uncovered two heterozygous mutations in NDUFV 2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT ‐ ND 1 ( MTND 1 ) gene (m.3946 G > A , p. E 214 K ). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III 2 /IV and I/III 2 ), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.