SLC25A22 is a novel gene for migrating partial seizures in infancy
Year: 2013
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: To identify a genetic cause for migrating partial seizures in infancy (MPSI). METHODS: We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22. RESULTS: In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport. INTERPRETATION: We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22.
Source: Annals of Neurology
DOI: 10.1002/ana.23998
Authors: Annapurna Poduri, Erin L. Heinzen, Vida Chitsazzadeh, Francesco Massimo Lasorsa, P. Christina Elhosary, Christopher M. LaCoursiere, Emilie Martin, Christopher J. Yuskaitis, Robert Sean Hill, Kutay Deniz Atabay, Brenda Barry, Jennifer N. Partlow, Fahad A. Bashiri, Radwan M. Zeidan, Salah A. Elmalik, Mohammad M. U. Kabiraj, Sanjeev Kothare, Tommy Stödberg, Amy McTague, Manju A. Kurian, Ingrid E. Scheffer, A. James Barkovich, Ferdinando Palmieri, Mustafa A. Salih, Christopher A. Walsh
Institutions: Boston Children's Hospital, Harvard University, Duke University, Duke Medical Center, The University of Texas Health Science Center at Houston, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, University of Bari Aldo Moro, Howard Hughes Medical Institute, Manton Center for Orphan Disease Research, King Saud University, King Khalid University Hospital, Riyadh Armed Forces Hospital, Karolinska University Hospital, Great Ormond Street Hospital, University College London, Royal Children's Hospital, The University of Melbourne, Austin Health, University of California, San Francisco, University of California San Francisco Medical Center
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Simons Foundation, Nancy Lurie Marks Family Foundation, Dubai Harvard Foundation for Medical Research, National Institutes of Health, Manton Center for Orphan Disease Research, Boston Children's Hospital, National Institute on Aging, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke
Awards: G2929635525, ADCC Genomic Medicine Approach to MCI and Dementia, G421627756, G5000692785, Genetics of Familial Epilepsy Syndromes, Human Epilepsy Genetics - Neuronal Migration Disorders, Human autism genetics and activity dependent gene activation, Human Epilepsy Genetics - Mosaic Mutations in Focal Epilepsy, G926499950
OpenAlex ID: W2122628867