Hypomorphic variants of cationic amino acid transporter 3 in males with autism spectrum disorders

Abstract

Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-015-2057-3) contains supplementary material, which is available to authorized users.

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

“…This gene encodes a sodium-independent cationic amino acid transporter, CAT-3, which is a member of the solute carrier family 7 [Verrey et al, 2004]. Studies of CAT-3 expression in brain development are conflicting; however, a recent study reported expression in the mouse brain during embryonic development [Nava et al, 2015]. Variation in the SLC7A3 gene is sparse, and loss-of-function variants are completely absent in the ExAC database (http://exac.broadinstitute.org/ gene/ENSG00000165349), demonstrating the importance of a functioning CAT-3 protein.…”

Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis

“…ASD has been previously associated with homozygous mutations in gene solute carrier family 7, member 5 (SLC7A5) which encodes the large neutral amino acid transporter subunit-1 (hLAT-1); and in males, with rare holomorphic variants of cationic amino acid transporter-3 (CAT-3) mediating uptake of arginine, ornithine, and lysine. These transporters mediate amino acid uptake into the cells, including neurons [ 15 ].…”

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

“…SLC7A3 and VSIG4 were also upregulated in ASD and have been previously associated as putative ASD risk genes [42]. Rare missense variants have been found in ASD subjects at SLC7A3, which is a cationic amino acid transporter selectively expressed in brain [55]. Nonsense and splice site variants have been found in ASD subjects at VSIG4, a complement C3 receptor that functions in pathogen recognition and inhibition of helper T-cell activation [56][57][58].…”