High prevalence of SLC6A8 deficiency in X-linked mental retardation

Am J Hum Genet. 2004 Jul;75(1):97-105. doi: 10.1086/422102. Epub 2004 May 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Chromosomes, Human, X / genetics*
  • Creatine / metabolism
  • DNA Mutational Analysis
  • Female
  • Genetic Linkage / genetics
  • Humans
  • Male
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / genetics*
  • Mental Retardation, X-Linked / genetics*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Plasma Membrane Neurotransmitter Transport Proteins
  • Prevalence
  • Sequence Homology, Amino Acid


  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • SLC6A8 protein, human
  • Creatine