Lamin B1 duplications cause autosomal dominant leukodystrophy

Padiath, Quasar Saleem; Saigoh, Kazumasa; Schiffmann, Raphael; Asahara, Hideaki; Yamada, Takeshi; Koeppen, Anulf; Hogan, Kirk; Ptáček, Louis J.; Fu, Ying‐Hui

doi:10.1038/ng1872

Cited by 362 publications

(354 citation statements)

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“…The genetic basis of the disease became known after initiating this study,6, 17 and two asymptomatic subjects without MRI pathology were found to be noncarriers of the LMNB1 duplication. These two individuals were excluded from the study.…”

Section: Methodsmentioning

confidence: 99%

“…This type of ADLD is caused by a duplication of the lamin B1 gene ( LMNB1 ) and increased expression of lamin B1,6, 7 which, in turn, seems to affect maturation of oligodendrocytes 8. Cases have been reported from Brazil, Canada, France, Germany, Ireland, Israel, Italy, Japan, Serbia, Sweden, and the United States, among other countries 6, 7, 9, 10, 11, 12, 13, 14, 15, 16.…”

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confidence: 99%

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LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

Finnsson

Sundblom

Dahl

et al. 2015

Annals of Neurology

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ObjectiveDuplication of the LMNB1 gene encoding lamin B1 causes adult‐onset autosomal‐dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1‐related ADLD.MethodsTwenty‐three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years.ResultsPathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset.Interpretation LMNB1‐related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia. Ann Neurol 2015;78:412–425

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

Finnsson

Sundblom

Dahl

et al. 2015

Annals of Neurology

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“…However, autosomal-dominant leukodystrophy, a neurodegenerative disease caused by myelin loss in the central nervous system, was recently found to be associated with a duplication of the lamin B1 gene. It is not clear how duplication of how the lamin B1 gene results in such a tissue-specific disease, although it was suggested that such an alteration may lead to the generation of autoantibodies resulting in demyelination [63].…”

Section: Laminopathies Associated With Mutations In the B-type Laminsmentioning

confidence: 99%

Mouse models of the laminopathies

Stewart

Kozlov

Fong

et al. 2007

Experimental Cell Research

107

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The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A-type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the Atype lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

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“…Mutations in B‐type lamins have also been described, enlarging the field of laminopathies. Thus, heterozygous mutations in LMNB2 have been reported to predispose to the development of acquired partial lipodystrophy (APLD), also called “Barraquer‐Simons syndrome” (Hegele et al., 2006), and duplication of LMNB1 leads to adult‐onset autosomal‐dominant leukodystrophy (ADLD; Padiath et al., 2006). …”

Section: Lamins and Laminopathiesmentioning

confidence: 99%

“…The autosomal‐dominant leukodystrophy (ADLD, OMIM # 169500) is the only laminopathy currently linked to the gene LMNB1, mainly caused by its duplication (Padiath et al., 2006). Clinically, this disease is a progressive degenerative neurological disorder with cerebellar, autonomic, and pyramidal abnormalities.…”

Section: Mirnas In Hereditary Laminopathiesmentioning

confidence: 99%

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

et al. 2018

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SummaryHereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue‐specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson–Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR‐9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation.

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Lamin B1 duplications cause autosomal dominant leukodystrophy

Cited by 362 publications

References 48 publications

LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

Mouse models of the laminopathies

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

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