Research Article

Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application†

  1. Efraim H. Rosenberg1,
  2. Cristina Martínez Muñoz1,
  3. Ofir T. Betsalel1,
  4. Silvy J.M. van Dooren1,
  5. Matilde Fernandez1,
  6. Cornelis Jakobs1,
  7. Ton J. deGrauw2,
  8. Tjitske Kleefstra3,
  9. Charles E. Schwartz4,
  10. Gajja S. Salomons1,*

Article first published online: 26 APR 2007

DOI: 10.1002/humu.20532

Issue

Human Mutation

Human Mutation

Volume 28, Issue 9, pages 890–896, September 2007

Additional Information

How to Cite

Rosenberg, E. H., Martínez Muñoz, C., Betsalel, O. T., van Dooren, S. J., Fernandez, M., Jakobs, C., deGrauw, T. J., Kleefstra, T., Schwartz, C. E. and Salomons, G. S. (2007), Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Human Mutation, 28: 890–896. doi: 10.1002/humu.20532

Author Information

  1. 1

    Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands

  2. 2

    Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

  3. 3

    Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

  4. 4

    J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina

*Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

  1. †

    Communicated by Ronald Wanders

Publication History

  1. Issue published online: 26 JUL 2007
  2. Article first published online: 26 APR 2007
  3. Manuscript Accepted: 6 MAR 2007
  4. Manuscript Received: 22 SEP 2006

Funded by

  • Dutch Society for Scientific Research (ZonMW/NWO). Grant Number: VIDI 917.56.349

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Keywords:

  • SLC6A8;
  • creatine transporter;
  • mental retardation;
  • diagnostic;
  • site directed mutagenesis;
  • solute carrier

Abstract

Creatine transporter deficiency is an X-linked mental retardation disorder caused by mutations in the creatine transporter gene (SLC6A8). So far, 20 mutations in the SLC6A8 gene have been described. We have developed a diagnostic assay to test creatine uptake in fibroblasts. Additionally, we expanded the assay to characterize novel SLC6A8 missense variants. A total of 13 variants were introduced in the SLC6A8 cDNA by site-directed mutagenesis. All variants were transiently transfected in SLC6A8-deficient fibroblasts and tested for restoration of creatine uptake in deficient primary fibroblasts. Thus, we proved that nine variants (p.Gly87Arg, p.Phe107del, p.Tyr317X, p.Asn336del, p.Cys337Trp, p.Ile347del, p.Pro390Leu, p.Arg391Trp, and p.Pro554Leu) are pathogenic mutations and four variants (p.Lys4Arg, p.Gly26Arg, p.Met560Val, and p.Val629Ile) are nonpathogenic. The present study provides an improved diagnostic tool to classify sequence variants of unknown significance. Hum Mutat 28(9), 890–896, 2007. © 2007 Wiley-Liss, Inc.

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