SLC25A22 is a novel gene for migrating partial seizures in infancy

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 (SNP) 500K data to identify regions with evidence for 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 two individuals with MPSI, we identified two 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 one 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 transmembraine 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 neonatal epilepsy with suppression bursts on EEG, we have expanded the phenotypic spectrum associated with SLC25A22.

AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate

“…Recognized genes function as ion channels (SCN1A, SCN2A, SCN8A, KCNQ2, KCNT2), transcription factors (ARX, ARHGEF9, CDKL5, PLCB1), synaptic proteins (PNKP, PCDH19, SPTAN1, STXBP1), a mitochondrial glutamate symporter that transports glutamate and a hydrogen ion across the inner mitochondrial membrane (SLC25A22), and now another gene associated with inner mitochondrial membrane glutamate transport (SLC25A12). While SLC25A22 mutation patients manifest both early myoclonic epilepsy and ohtahara-type early epileptic encephalopathy (Molinari et al 2005(Molinari et al , 2009Poduri et al 2013), the SLC25A12 mutation patients' epilepsy resembles instead the non-myoclonic variant. Overall, this report establishes SLC25A12 as a likely early-onset epileptic encephalopathy gene and emergence of altered glutamate handling as a functional subclass.…”

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

“…Mutations in SLC25A22 encoding a mitochondrial inner membrane glutamate carrier have been reported in several families with severe epilepsy syndromes, presenting as early myoclonic epilepsy with burst suppression or migrating partial seizures of infancy [43][44][45][46]. The SLC25A22 glutamate/H+ symporter is particularly abundant in astrocytes; thus, possible disease mechanisms include accumulation of glutamate in astrocytes, dysregulation of extracellular glutamate levels, and abnormal neurotransmission following activation of extrasynaptic glutamate receptors [43].…”

The Genetics of the Epilepsies

“…While KCNT1 mutations account for about one third of reported cases of EIMFS, the other genetically defined cases are caused by mutations in a number of other genes (SCN1A, SLC25A22, PLCB1, TBC1D24, SCN2A, QARS, SCN8A) [25,[55][56][57][58][59][60][61].…”