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Lookup NU author(s): Dr Ingrid Verhaart, Professor Annemieke Aartsma-Rus
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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.
Author(s): deBrouwer AP, Nabuurs SB, Verhaart IE, Oudakker AR, Hordijk R, Yntema HG, Hordijk-Hos JM, Voesenek K, deVries BB, vanEssen T, Chen W, Hu H, Chelly J, denDunnen JT, Kalscheuer VM, AartsmaRus AM, Hamel BC, vanBokhoven H, Kleefstra T
Publication type: Article
Publication status: Published
Journal: European Journal of Human Genetics
Year: 2014
Volume: 22
Issue: 4
Pages: 480-485
Online publication date: 31/07/2013
Acceptance date: 02/07/2013
ISSN (print): 1018-4813
ISSN (electronic): 1476-5438
Publisher: Macmillan Publishers Limited
URL: http://dx.doi.org/10.1038/ejhg.2013.169
DOI: 10.1038/ejhg.2013.169
PubMed id: 23900271
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