Lamin B1 duplications cause autosomal dominant leukodystrophy.
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.
Padiath
Quasar S
QS
Department of Neurology, University of California, San Francisco, San Francisco, California 94158, USA.
Saigoh
Kazumasa
K
Schiffmann
Raphael
R
Asahara
Hideaki
H
Yamada
Takeshi
T
Koeppen
Anulf
A
Hogan
Kirk
K
Ptácek
Louis J
LJ
Fu
Ying-Hui
YH
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D005799:Genes, Dominant; D008040:Genetic Linkage; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D034921:Lamin Type B / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data
D034921:Lamin Type B