Homozygous loss of function mutations or deletions in SLC1A1.
Molecular characteristics.
In a 2011 study carried out by Bailey and colleagues, in 2 brothers with dicarboxylic aminoaciduria, a homozygous missense mutation in exon 12 of SLC1A1was found, resulting in an arginine to tryptophan substitution at position 445 (R445W). Unaffected family members were heterozygous for the mutation. In the second proband, a homozygous 3-bp deletion was found in exon 10, resulting in deletion of isoleucine at position 395 (l395del). The parents were heterozygous for the mutation. In a 2019 study, Doan and colleagues identified an autistic individual bearing a homozygous loss of function mutation in SLC1A1. The affected individual bore a homozygous c.G142T: p.E48X change. The parents were heterozygous for the mutation.
Pathophysiologic mechanism.
Both the R445W and l395del mutations occur in regions of SLC1A1that are functionally important for substrate (glutamate and aspartate) binding and transport. The mutations also result in nearly (R445W) or fully (l395del) abolished cell surface expression of SLC1A1in the proximal tube of kidney. The failure of this renal reabsorption mechanism leads to elevated urinary glutamate and aspartate levels.
Diagnostic testing.
Dicarboxylic aminoaciduria is diagnosed by finding increased glutamate and aspartate levels in the urine. Molecular genetic tests, including sequence analysis of the entire SLC1A1coding region, deletion analysis, and targeted variant analysis, could be pursued via targeted sequencing or would be captured in whole exome or whole genome sequencing.
Heterozygous deletion of SLC1A1.
Molecular characteristics.
In a 2013 study of 7 affected member of a 5-generation Palauan family, Myles-Worsley and colleagues identified a 84k-bp deletion occurring immediately upstream of the SLC1A1gene in a regulatory region containing the full native promotor sequence that extended through exon 1, resulting in removal of one of the domains responsible for glutamate transport.
Pathophysiologic mechanism.
Dysregulation of glutamate transmission has been hypothed to contribute to a subset of pathologic mechanisms of schizophrenia. However, given that SLC1A1has not been identified in genome wide association in schizophrenia, the role of SLC1A1in schizophrenia or other psychotic disorders remains uncertain to date.
SLC1A1