Lamin B1 duplications cause autosomal dominant leukodystrophy

Nat Genet. 2006 Oct;38(10):1114-23. doi: 10.1038/ng1872. Epub 2006 Sep 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Brain / pathology
  • Brain / physiology
  • Cells, Cultured
  • DNA Mutational Analysis
  • Drosophila melanogaster / genetics
  • Female
  • Gene Dosage
  • Gene Duplication*
  • Genes, Dominant*
  • Genetic Linkage
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Hereditary Central Nervous System Demyelinating Diseases / pathology
  • Humans
  • Lamin Type B / genetics*
  • Male
  • Molecular Sequence Data

Substances

  • Lamin Type B
  • lamin B1