Whole-Exome Sequencing Identifies a Variant of the Mitochondrial MT-ND1 Gene Associated with Epileptic Encephalopathy: West Syndrome Evolving to Lennox-Gastaut Syndrome

• Published in: Human mutation Vol. 34; no. 12; pp. 1623 - 1627
• Main Authors: Delmiro, Aitor, Rivera, Henry, García-Silva, María Teresa, García-Consuegra, Inés, Martín-Hernández, Elena, Quijada-Fraile, Pilar, de Las Heras, Rogelio Simón, Moreno-Izquierdo, Ana, Martín, Miguel Ángel, Arenas, Joaquín, Martínez-Azorín, Francisco
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2013; Hindawi Limited
• Subjects: Amino Acid Sequence; DNA Mutational Analysis; Exome; Female; Fibroblasts; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Infant; Intellectual Disability - genetics; Intellectual Disability - metabolism; Lennox Gastaut Syndrome; Mitochondrial DNA; Molecular Sequence Data; MT-ND1or MTND1; Mutation; NADH Dehydrogenase - chemistry; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Proteins; ROS; Sequence Alignment; Spasms, Infantile - genetics; Spasms, Infantile - metabolism; West syndrome; West syndrome; Lennox-Gastaut syndrome; MT-ND1or MTND1; ROS
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22445

ABSTRACT We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox–Gastaut 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 NDUFV2 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‐ND1 (MTND1) gene (m.3946G>A, p.E214K). 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/III2/IV and I/III2), 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. We describe a heteroplasmic mutation in mitochondrial gene MT‐ND1 (m.3946G>A, p.E214K), which was identified using data from single whole‐exome sequencing and that is strongly suggested to cause epileptic encephalopathy (West syndrome evolving to Lennox–Gastaut syndrome). The expression of the gene was not affected but the protein level was significantly reduced. This reduction have an impact on the assembly of the complex I and supercomplexes, leading to mitochondrial complex I deficiency and a significant increase of ROS produced by this complex.