Abstract
Mutations in the creatine transporter gene, SLC6A8 (MIM 30036), located in Xq28, have been found in families with X-linked mental retardation (XLMR) as well as in males with idiopathic mental retardation (MR). In order to estimate the frequency of such mutations in the MR population, a screening of 478 males with MR of unknown cause was undertaken. All 13 exons of SLC6A8 were sequenced using genomic DNA. Six novel potentially pathogenic mutations were identified that were not encountered in at least 588 male control chromosomes: two deletions (p.Asn336del, p.Ile347del) and a splice site alteration (c.1016+2C>T) are considered pathogenic based on the nature of the variant. A mutation (p.Arg391Trp) should be considered pathogenic owing to its localization in a highly conserved region. Two other missense variants (p.Lys4Arg, p.Gly26Arg) are not conserved but were not observed in over 300 male control chromosomes. Their pathogenicity is uncertain. A missense variant (p.Val182Met), was classified as a polymorphism based on a normal creatine/creatinine (Cr:Crn) ratio and cerebral creatine signal in proton magnetic resonance spectroscopy (H-MRS) in the patient. Furthermore, we found 14 novel intronic and neutral variants that were not encountered in at least 280 male control chromosomes and should be considered as unclassified variants. Our findings of a minimum of four pathogenic mutations and two potentially pathogenic mutations indicate that about 1% of males with MR of unknown etiology might have a SLC6A8 mutation. Thus, DNA sequence analysis and/or a Cr:Crn urine screen is warranted in any male with MR of unknown cause.
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Acknowledgements
The research was supported by grants HD26202 from NICHD (CES), MH57840 from NIMH (RES and CES) and a grant from the South Carolina Department of Disabilities and Special Needs. EHR and GSS are financially supported by ZonMW/NWO grant 917.56.349). Yodit Jacob is acknowledged for her technical support. The manuscript was prepared by Joy Driggers. This paper is dedicated to the memory of Ethan Francis Schwartz (1996–1998).
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Amy J. Clark and Efraim H. Rosenberg have contributed equally to this work.
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Clark, A.J., Rosenberg, E.H., Almeida, L.S. et al. X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet 119, 604–610 (2006). https://doi.org/10.1007/s00439-006-0162-9
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DOI: https://doi.org/10.1007/s00439-006-0162-9