title: 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.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.|Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rupp
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Boissel
authors.affiliation: Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.|Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.|Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Paris, France.|Service de neuropédiatrie, Hôpital Trousseau, AP-HP, Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rastetter
authors.affiliation: Service de psychiatrie de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Amiet
authors.affiliation: Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.|Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.|Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Paris, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Jacquette
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Dupuits
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouteiller
authors.affiliation: Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.affiliation: Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Faudet
authors.affiliation: Service de neuropédiatrie, Hôpital Trousseau, AP-HP, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.affiliation: Service de psychiatrie de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Philippe
authors.affiliation: Service de psychiatrie de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, AP-HP, 75013, Paris, France.|Centre Diagnostic Autisme de l'Hôpital Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Périsse
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.|Service de psychiatrie de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Laurent
authors.affiliation: Institut Cochin, Inserm U567, UMR 8104, Université René Descartes, Paris 5, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.affiliation: Bioinformatics and Biostatistics Core Facility (iCONICS), Institut du cerveau et de la moelle épinière (ICM), Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Guillemot
authors.affiliation: Institut Cochin, Inserm U567, UMR 8104, Université René Descartes, Paris 5, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Service de psychiatrie de l'enfant et de l'adolescent, Hôpital Pitié-Salpêtrière, AP-HP, 75013, Paris, France.|Institut des Systèmes Intelligents et Robotiques, CNRS UMR 7222, UPMC-Paris-6, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.|Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.|Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Paris, France.|Service de neuropédiatrie, Hôpital Trousseau, AP-HP, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France.|Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Closs
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, 75013, Paris, France. christel.depienne@upmc.fr.|INSERM, U 1127, 75013, Paris, France. christel.depienne@upmc.fr.|CNRS, UMR 7225, 75013, Paris, France. christel.depienne@upmc.fr.|Institut du cerveau et de la moelle épinière (ICM), 75013, Paris, France. christel.depienne@upmc.fr.|Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, AP-HP, 75013, Paris, France. christel.depienne@upmc.fr.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
mesh_terms: D000595:Amino Acid Sequence; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics*; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D019921:Biotinylation; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D014982:Xenopus laevis; D027201:Cationic Amino Acid Transporter 1
chemical_list: D026923:Amino Acid Transport Systems, Basic; C499482:SLC7A3 protein, human; D027201:Cationic Amino Acid Transporter 1
keywords: Autism spectrum disorders; Cationic amino acid transporter; Chromosome X; Exome sequencing; Oligogenism