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Eur J Hum Genet. 2014 Apr;22(4):480-5. doi: 10.1038/ejhg.2013.169. Epub 2013 Jul 31.

A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy.

Author information

1
1] Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [2] Institute of Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [3] Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
2
Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
3
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
4
1] Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [2] Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
5
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
6
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
7
1] Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [2] Institute of Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
8
Department Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
9
Institut Cochin, INSERM Unité 1016, CNRS UMR 8104, Paris, France.

Abstract

We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.

PMID:
23900271
PMCID:
PMC3953899
DOI:
10.1038/ejhg.2013.169
[Indexed for MEDLINE]
Free PMC Article

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