دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.
المؤلفون: Iqbal Z; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., Willemsen MH; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., Papon MA; INSERM U930, Tours 37032, France; University François-Rabelais, UMR 930 'Imaging and Brain,' Tours 37032, France., Musante L; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany., Benevento M; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., Hu H; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany., Venselaar H; Centre for Molecular and Biomolecular Informatics, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., Wissink-Lindhout WM; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., Vulto-van Silfhout AT; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., Vissers LE; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., de Brouwer AP; 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., Marouillat S; INSERM U930, Tours 37032, France; University François-Rabelais, UMR 930 'Imaging and Brain,' Tours 37032, France., Wienker TF; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany., Ropers HH; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany., Kahrizi K; Social Welfare and Rehabilitation University, Tehran 19857-13834, Iran., Nadif Kasri N; 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., Najmabadi H; Social Welfare and Rehabilitation University, Tehran 19857-13834, Iran., Laumonnier F; 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., Kleefstra T; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, the Netherlands., van Bokhoven H; 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: hans.vanbokhoven@radboudumc.nl.
المصدر: American journal of human genetics [Am J Hum Genet] 2015 Mar 05; Vol. 96 (3), pp. 386-96. Date of Electronic Publication: 2015 Feb 19.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
أسماء مطبوعة: Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.
مواضيع طبية MeSH: Homozygote*, Amino Acid Transport Systems/*genetics , Intellectual Disability/*genetics , Mental Disorders/*genetics , Plasma Membrane Neurotransmitter Transport Proteins/*genetics , Speech Disorders/*genetics , Tremor/*genetics, Amino Acid Sequence ; Animals ; Chromosome Mapping ; DNA Copy Number Variations ; Exome ; Female ; Hippocampus/cytology ; Hippocampus/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Molecular Sequence Data ; Mutation ; Pedigree ; Phenotype ; Transfection ; Young Adult
مستخلص: 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.
(Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
التعليقات: Comment in: Clin Genet. 2015 Aug;88(2):136-7. (PMID: 25970702)
References: Arch Neurol. 1999 Jul;56(7):807-8. (PMID: 10404981)
Clin Genet. 2014 Feb;85(2):101-10. (PMID: 23895455)
BMC Neurosci. 2013;14:54. (PMID: 23672601)
Adv Biochem Psychopharmacol. 1976;15:165-73. (PMID: 15411)
Nature. 2014 Jul 17;511(7509):344-7. (PMID: 24896178)
Ment Retard Dev Disabil Res Rev. 2002;8(3):117-34. (PMID: 12216056)
Proteins. 2002 May 15;47(3):393-402. (PMID: 11948792)
J Mol Graph. 1990 Mar;8(1):52-6, 29. (PMID: 2268628)
Mol Pharmacol. 2008 Dec;74(6):1521-32. (PMID: 18768736)
Brain Res. 2006 Feb 16;1073-1074:311-5. (PMID: 16458270)
FEBS Lett. 1993 Jan 4;315(2):114-8. (PMID: 8093354)
Eur J Hum Genet. 2011 May;19(5):597-601. (PMID: 21248743)
Brain Res. 2009 Feb 9;1253:176-83. (PMID: 19070606)
Methods. 2001 Dec;25(4):402-8. (PMID: 11846609)
Neurochem Int. 2006 May-Jun;48(6-7):559-67. (PMID: 16540203)
Nature. 2011 Oct 6;478(7367):57-63. (PMID: 21937992)
Nat Struct Mol Biol. 2009 Jun;16(6):652-7. (PMID: 19430461)
Neuropsychopharmacology. 1999 Feb;20(2):106-18. (PMID: 9885791)
Dev Med Child Neurol. 1997 Feb;39(2):125-32. (PMID: 9062428)
Am J Hum Genet. 2001 Jun;68(6):1497-500. (PMID: 11326334)
Annu Rev Genomics Hum Genet. 2010;11:161-87. (PMID: 20822471)
Annu Rev Genet. 2011;45:81-104. (PMID: 21910631)
Nat Genet. 2010 Dec;42(12):1109-12. (PMID: 21076407)
Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512)
Proteins. 2009;77 Suppl 9:114-22. (PMID: 19768677)
J Med Genet. 2013 Dec;50(12):802-11. (PMID: 24123876)
Hum Mutat. 2009 Aug;30(8):1237-44. (PMID: 19514061)
Pflugers Arch. 2004 Feb;447(5):519-31. (PMID: 12719981)
Hum Mutat. 2010 Apr;31(4):494-9. (PMID: 20151403)
Cancer Res. 2005 Jul 15;65(14):6071-9. (PMID: 16024607)
J Neural Transm (Vienna). 1996;103(5):555-60. (PMID: 8811501)
Methods Mol Biol. 2000;132:365-86. (PMID: 10547847)
J Biol Chem. 2009 Mar 27;284(13):8439-48. (PMID: 19147495)
J Clin Invest. 2005 Mar;115(3):774-9. (PMID: 15765150)
Genome Med. 2013 Feb 05;5(2):11. (PMID: 23383720)
Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276)
Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901)
Trends Genet. 2014 Jan;30(1):32-9. (PMID: 24176302)
Pharmacol Rev. 2011 Sep;63(3):585-640. (PMID: 21752877)
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4. (PMID: 12824425)
Brain Res Bull. 2013 Apr;93:110-9. (PMID: 23266673)
Brain Res. 1982 May 13;239(2):479-88. (PMID: 6124304)
Hum Mutat. 2014 Dec;35(12):1427-35. (PMID: 25219469)
Hum Hered. 2014;77(1-4):150-60. (PMID: 25060278)
Annu Rev Med. 2013;64:441-50. (PMID: 23020879)
المشرفين على المادة: 0 (Amino Acid Transport Systems)
0 (Plasma Membrane Neurotransmitter Transport Proteins)
0 (SLC6A17 protein, human)
تواريخ الأحداث: Date Created: 20150224 Date Completed: 20150512 Latest Revision: 20200824
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4375531
DOI: 10.1016/j.ajhg.2015.01.010
PMID: 25704603
قاعدة البيانات: MEDLINE
الوصف
تدمد:1537-6605
DOI:10.1016/j.ajhg.2015.01.010