Lamin B1 duplications cause autosomal dominant leukodystrophy

A Corrigendum to this article was published on 01 February 2007

This article has been updated

Abstract

NOTE: The construct we described as moody-GAL4 has a name that was assigned to a different construct in a previously published paper. In this paper, it should be referred to as SPG-GAL4 (for 'sub-perineural-glia-GAL4'). This construct was a gift from R. Bainton (University of California San Francisco School of Medicine). The construction and activity of this promoter will be published elsewhere (R. Bainton, personal communication). The error has been corrected in the PDF version of the article.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis.

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Figure 1: Pedigree charts of ADLD families.
Figure 2: Identification of a duplicated genomic segment within the critical region.
Figure 3: Quantification and confirmation of the genomic copy number mutation.
Figure 4: Mapping duplication junctions in affected individuals using the allele peak height ratio assay.
Figure 5: Schematic representation showing genomic structure of the duplications.
Figure 6: Lamin B1 shows increased expression in brain tissue from affected individuals.
Figure 7: Lamin B1 overexpression in the D. melanogaster eye and cell lines.

Change history

  • 12 September 2006

    In the version of this article initially published online, the name of one of the authors, Raphael Schiffmann, was misspelled. The error has been corrected for all versions of the article.

  • 22 January 2007

    The construct we described as moody-GAL4 has a name that was assigned to a different construct in a previously published paper. In this paper, it should be referred to as SPG-GAL4 (for ‘sub-perineural-glia-GAL4’). This construct was a gift from R. Bainton (University of California San Francisco School of Medicine). The construction and activity of this promoter will be published elsewhere (R. Bainton, personal communication). The error has been corrected in the PDF version of the article.

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Acknowledgements

The authors thank the individuals with ADLD and their families for participating in this research. We would like to thank M. Krasnow and R. Bainton for fly stocks and J. Ellenberg for the pEGFP-lamin B1 construct. We are grateful to J. Rawson for fly injections and H.-Y. Lee for confocal microscopy assistance. We thank S. Hauser and J. Oksenberg for discussions. We acknowledge members of the Fu and Ptáček labs for technical assistance and discussions. This work was supported by US National Institutes of Health grant NS41331 (Y.-H.F.), a Sandler Neurogenetics grant (Y.-H.F) and a Pilot grant from the Multiple Sclerosis society (L.J.P.). L.J.P. holds the John C. Coleman Distinguished Professorship in Neurodegenerative Diseases and is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Ying-Hui Fu.

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Supplementary information

Supplementary Table 1

List of known genes screened for mutations in the ADLD critical region. (PDF 71 kb)

Supplementary Table 2

Summary of relative lamin B1 expression in patient brain tissues. (PDF 89 kb)

Supplementary Table 3

List of primers and probes used. (PDF 83 kb)

Supplementary Methods (PDF 104 kb)

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Padiath, Q., Saigoh, K., Schiffmann, R. et al. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38, 1114–1123 (2006). https://doi.org/10.1038/ng1872

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