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

Am J Hum Genet. 2015 Mar 5;96(3):386-96. doi: 10.1016/j.ajhg.2015.01.010.

Zafar Iqbal ¹, Marjolein H Willemsen ¹, Marie-Amélie Papon ², Luciana Musante ³, Marco Benevento ⁴, Hao Hu ³, Hanka Venselaar ⁵, Willemijn M Wissink-Lindhout ¹, Anneke T Vulto-van Silfhout ¹, Lisenka E L M Vissers ¹, Arjan P M de Brouwer ⁶, Sylviane Marouillat ², Thomas F Wienker ³, Hans Hilger Ropers ³, Kimia Kahrizi ⁷, Nael Nadif Kasri ⁶, Hossein Najmabadi ⁷, Frédéric Laumonnier ⁸, Tjitske Kleefstra ¹, Hans van Bokhoven ⁹

Affiliations

1 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
2 INSERM U930, Tours 37032, France; University François-Rabelais, UMR 930 "Imaging and Brain," Tours 37032, France.
3 Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
4 Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
5 Centre for Molecular and Biomolecular Informatics, Radboud university medical center, Nijmegen 6500 HB, the Netherlands.
6 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.
7 Social Welfare and Rehabilitation University, Tehran 19857-13834, Iran.
8 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.
9 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: [email protected].

PMID: 25704603 DOI: 10.1016/j.ajhg.2015.01.010

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.

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