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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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http://www.ncbi.nlm.nih.gov/pubmed/25704603 (beliebiger Volltext)
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 Urheber:
Iqbal, Z., Autor
Willemsen, M. H., Autor
Papon, M. A., Autor
Musante, L.1, Autor           
Benevento, M., Autor
Hu, H.1, Autor
Venselaar, H., Autor
Wissink-Lindhout, W. M., Autor
Vulto-van Silfhout, A. T., Autor
Vissers, L. E., Autor
de Brouwer, A. P., Autor
Marouillat, S., Autor
Wienker, T. F.2, Autor           
Ropers, H. H.1, Autor           
Kahrizi, K., Autor
Nadif Kasri, N., Autor
Najmabadi, H., Autor
Laumonnier, F., Autor
Kleefstra, T., Autor
van Bokhoven, H., Autor
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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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.

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Sprache(n): eng - English
 Datum: 2015-02-192015-03-05
 Publikationsstatus: Erschienen
 Seiten: 11
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
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 Identifikatoren: DOI: 10.1016/j.ajhg.2015.01.010
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
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Titel: The American Journal of Human Genetics
  Andere : Am. J. Hum. Genet.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: American Society of Human Genetics
Seiten: - Band / Heft: 96 (3) Artikelnummer: - Start- / Endseite: 386 - 396 Identifikator: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1