ausblenden:
Schlagwörter:
Amino Acid Sequence
Amino Acid Transport Systems/*genetics
Animals
Chromosome Mapping
DNA Copy Number Variations
Exome
Female
Hippocampus/cytology/metabolism
*Homozygote
Humans
Intellectual Disability/*genetics
Male
Mental Disorders/*genetics
Mice
Mice, Inbred C57BL
Middle Aged
Molecular Sequence Data
Mutation
Pedigree
Phenotype
Plasma Membrane Neurotransmitter Transport Proteins/*genetics
Speech Disorders/*genetics
Transfection
Tremor/*genetics
Young Adult
Zusammenfassung:
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.