Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.

Iqbal Z1, Willemsen MH1, Papon MA2, Musante L3, Benevento M4, Hu H3, Venselaar H5, Wissink-Lindhout WM1, Vulto-van Silfhout AT1, Vissers LE1, de Brouwer AP6, Marouillat S2, Wienker TF3, Ropers HH3, Kahrizi K7, Nadif Kasri N6, Najmabadi H7, Laumonnier F8, Kleefstra T1, van Bokhoven H9.
Source: Am J Hum Genet
Publication Date: (2015)
Issue: 96(3): 386-396
Research Area:
Basic Research
Cells used in publication:
Neuron, hippocampal, mouse
Species: mouse
Tissue Origin: brain
Neuron, cortical, mouse
Species: mouse
Tissue Origin: brain
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.