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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 225160.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
High prevalence of SLC6A8 deficiency in X-linked mental retardation
Authors:Rosenberg, Efraim H.; Almeida, Ligia S.; Kleefstra, Tjitske; deGrauw, Rose S.; Yntema, Helger G.; Bahi, Nadia; Moraine, Claude; Ropers, Hans-Hilger; Fryns, Jean-Pierre; deGrauw, Ton J.; Jakobs, Cornelis; Salomons, Gajja S.
Date of Publication (YYYY-MM-DD):2004-05-20
Title of Journal:American Journal of Human Genetics
Journal Abbrev.:Am. J. Hum. Genet.
Start Page:97
End Page:105
Copyright:© 2004 by The American Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description:A novel X-linked mental retardation (XLMR) syndrome was recently identified, resulting from creatine deficiency in the brain caused by mutations in the creatine transporter gene, SLC6A8. We have studied the prevalence of SLC6A8 mutations in a panel of 290 patients with nonsyndromic XLMR archived by the European XLMR Consortium. The full-length open reading frame and splice sites of the SLC6A8 gene were investigated by DNA sequence analysis. Six pathogenic mutations, of which five were novel, were identified in a total of 288 patients with XLMR, showing a prevalence of at least 2.1% (6/288). The novel pathogenic mutations are a nonsense mutation (p.Y317X) and four missense mutations. Three missense mutations (p.G87R, p.P390L, and p.P554L) were concluded to be pathogenic on the basis of conservation, segregation, chemical properties of the residues involved, as well as the absence of these and any other missense mutation in 276 controls. For the p.C337W mutation, additional material was available to biochemically prove (i.e., by increased urinary creatine : creatinine ratio) pathogenicity. In addition, we found nine novel polymorphisms (IVS1+26G→A, IVS7+37G→A, IVS7+87A→G, IVS7-35G→A, IVS12-3C→T, IVS2+88G→C, IVS9-36G→A, IVS12-82G→C, and p.Y498) that were present in the XLMR panel and/or in the control panel. Two missense variants (p.V629I and p.M560V) that were not highly conserved and were not associated with increased creatine : creatinine ratio, one translational silent variant (p.L472), and 10 intervening sequence variants or untranslated region variants (IVS6+9C→T, IVS7-151_152delGA, IVS7-99C→A, IVS8-35G→A, IVS8+28C→T, IVS10-18C→T, IVS11+21G→A, IVS12+15C→T, *207G→C, IVS12+32C→A) were found only in the XLMR panel but should be considered as unclassified variants or as a polymorphism (p.M560V). Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome.
Comment of the Author/Creator:# BLAST, http://www.ncbi.nlm.nih.gov/BLAST/ First citation in article
# European XLMR Consortium, http://www.euromrx.com/ First citation in article
# GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for SLC6A8 [accession number Z66539]) First citation in article
# Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for SLC6A8, AGAT deficiency, GAMT deficiency, and SLC6A8 deficiency)
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands;
Department of Human Genetics, University Medical Center, Nijmegen, The Netherlands;
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, USA;
Institut Cochin de Génétique Moleculaire, Centre National de la Recherche Scientifique/INSERM, CHU Cochin, Paris, France; Service de Génétique—INSERM U316, CHU Bretonneau, Tours, France;
Center for Human Genetics, Clinical Genetics Unit, Leuven, Belgium;
The European X-Linked Mental Retardation (XLMR) Consortium
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