Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

• Published in: American journal of human genetics Vol. 96; no. 3; pp. 386 - 396
• Main Authors: Iqbal, Zafar, Willemsen, Marjolein H., Papon, Marie-Amélie, Musante, Luciana, Benevento, Marco, Hu, Hao, Venselaar, Hanka, Wissink-Lindhout, Willemijn M., Vulto-van Silfhout, Anneke T., Vissers, Lisenka E.L.M., de Brouwer, Arjan P.M., Marouillat, Sylviane, Wienker, Thomas F., Ropers, Hans Hilger, Kahrizi, Kimia, Nadif Kasri, Nael, Najmabadi, Hossein, Laumonnier, Frédéric, Kleefstra, Tjitske, van Bokhoven, Hans
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.03.2015; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Amino Acid Transport Systems - genetics; Amino acids; Animals; Behavior disorders; Chromosome Mapping; Developmental disabilities; DNA Copy Number Variations; Exome; Female; Genomics; Hippocampus - cytology; Hippocampus - metabolism; Homozygote; Humans; Intellectual Disability - genetics; Male; Mental Disorders - genetics; Mice; Mice, Inbred C57BL; Middle Aged; Molecular Sequence Data; Morphology; Mutation; Pedigree; Phenotype; Plasma Membrane Neurotransmitter Transport Proteins - genetics; Speech disorders; Speech Disorders - genetics; Transfection; Tremor - genetics; Young Adult
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2015.01.010

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses.