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

Iqbal, Z., Willemsen, M. H., Papon, M. A., Musante, L., Benevento, M., Hu, H., et al. (2015). Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems. The American Journal of Human Genetics, 96(3), 386-396. doi:10.1016/j.ajhg.2015.01.010.

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© 2015 by The American Society of Human Genetics
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Iqbal, Z., Author
Willemsen, M. H., Author
Papon, M. A., Author
Musante, L.1, Author              
Benevento, M., Author
Hu, H.1, Author
Venselaar, H., Author
Wissink-Lindhout, W. M., Author
Vulto-van Silfhout, A. T., Author
Vissers, L. E., Author
de Brouwer, A. P., Author
Marouillat, S., Author
Wienker, T. F.2, Author              
Ropers, H. H.1, Author              
Kahrizi, K., Author
Nadif Kasri, N., Author
Najmabadi, H., Author
Laumonnier, F., Author
Kleefstra, T., Author
van Bokhoven, H., Author
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              
2Clinical Genetics (Thomas F. Wienker), Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385696              

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Free keywords: 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
 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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Language(s): eng - English
 Dates: 2015-02-192015-03-05
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.ajhg.2015.01.010
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 96 (3) Sequence Number: - Start / End Page: 386 - 396 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1