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

de Brouwer, A. P., Nabuurs, S. B., Verhaart, I. E., Oudakker, A. R., Hordijk, R., Yntema, H. G., et al. (2014). A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy. European journal of human genetics, 22(4), 480-485. doi:10.1038/ejhg.2013.169.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C2BC-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C2BD-7
Genre: Journal Article

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© 2014 European Society of Human Genetics
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 Creators:
de Brouwer, A. P., Author
Nabuurs, S. B., Author
Verhaart, I. E., Author
Oudakker, A. R., Author
Hordijk, R., Author
Yntema, H. G., Author
Hordijk-Hos, J. M., Author
Voesenek, K., Author
de Vries, B. B., Author
van Essen, T., Author
Chen, W.1, Author              
Hu, H.1, Author              
Chelly, J., Author
den Dunnen, J. T., Author
Kalscheuer, V. M.2, Author              
Aartsma-Rus, A. M., Author
Hamel, B. C., Author
van Bokhoven, H., Author
Kleefstra, T., Author
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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Free keywords: Adult Aged Base Pairing Cells, Cultured Dystroglycans/genetics Dystrophin/*genetics Exons Genetic Diseases, X-Linked/*genetics Genetic Loci Genotype Humans Intellectual Disability/*genetics Lod Score Male Muscular Dystrophies/genetics Mutation Pedigree Protein Conformation RNA, Messenger/genetics *Sequence Deletion
 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 beta-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.

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Language(s): eng - English
 Dates: 2013-07-312014-04
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/ejhg.2013.169
ISSN: 1476-5438 (Electronic)1018-4813 (Print)
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Title: European journal of human genetics
  Other : Eur. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 22 (4) Sequence Number: - Start / End Page: 480 - 485 Identifier: ISSN: 1018-4813
CoNE: https://pure.mpg.de/cone/journals/resource/954925585277_1