title: Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.
abstract: 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.
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: INSERM U930, Tours 37032, France; University François-Rabelais, UMR 930 "Imaging and Brain," Tours 37032, France.
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Musante
authors.affiliation: Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Benevento
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Willemijn M
authors.initials: WM
authors.lastname: Wissink-Lindhout
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.affiliation: INSERM U930, Tours 37032, France; University François-Rabelais, UMR 930 "Imaging and Brain," Tours 37032, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Marouillat
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Hans Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Social Welfare and Rehabilitation University, Tehran 19857-13834, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Nael
authors.initials: N
authors.lastname: Nadif Kasri
authors.affiliation: Social Welfare and Rehabilitation University, Tehran 19857-13834, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: INSERM U930, Tours 37032, France; University François-Rabelais, UMR 930 "Imaging and Brain," Tours 37032, France; Department of Human Genetics, Centre Hospitalier Régional Universitaire, Tours 37044, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Laumonnier
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical center, Nijmegen 6500 HB, the Netherlands. Electronic address: hans.vanbokhoven@radboudumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics*; D013064:Speech Disorders / Q000235:genetics*; D014162:Transfection; D014202:Tremor / Q000235:genetics*; D055815:Young Adult
chemical_list: D026905:Amino Acid Transport Systems; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C000597609:SLC6A17 protein, human