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Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab. (Forskargrupp Dahl)ORCID iD: 0000-0002-4383-9880
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab. (Forskargrupp Anneren)
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2011 (English)In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 1, 65-72 p.Article in journal (Refereed) Published
Abstract [en]

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

Place, publisher, year, edition, pages
2011. Vol. 12, no 1, 65-72 p.
Keyword [en]
Autonomic symptoms, Autosomal dominant leukodystrophy (ADLD), Duplication, Lamin B1, LMNB1
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-144612DOI: 10.1007/s10048-010-0269-yISI: 000286664500009PubMedID: 21225301OAI: oai:DiVA.org:uu-144612DiVA: diva2:393787
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2016-09-09Bibliographically approved
In thesis
1. Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease: Translational Studies of Two Neurogenetic Diseases
Open this publication in new window or tab >>Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease: Translational Studies of Two Neurogenetic Diseases
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a large variety of diseases caused by single-gene mutations. Although most of these conditions are rare, together they impose a significant burden to the population. This thesis describes clinical and genetic studies of two single-gene diseases:

1) Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) caused by LMNB1 gene duplications, and characterized by autonomic, pyramidal and cerebellar symptoms. Spinal cords of patients with ADLD were studied by MRI and found to be thin, with high signal intensity in white matter. Histopathology showed loss of myelinated fibres with some reactive gliosis. DNA samples from four different families with ADLD were obtained, and the LMNB1 gene was screened for duplications. Single nucleotide polymorphism array revealed LMNB1 duplications in all ADLD families. LMNB1 mRNA and protein levels were assessed in white blood cells using quantitative polymerase chain reaction and Western blot, and increased levels of LMNB1 mRNA and lamin B1 protein could be demonstrated. We concluded that spinal cord atrophy in patients with ADLD is a valuable differential diagnostic sign, and that increased levels of LMNB1 can be detected in peripheral blood.

2) Rippling muscle disease (RMD) is caused by CAV3 gene mutations. Clinical features are percussion-induced muscle mounding, –rapid contractions and undulating muscle contractions (rippling). The CAV3 gene was sequenced in 38 members of a family with RMD. Twenty-two individuals had clinical features of RMD. No muscle weakness was seen. All patients with signs of RMD carried the p.A46T CAV3 mutation, showing that the p.A46T mutation was benign and that the diagnosis can be made clinically. In vitro contracture test results from 10 of the subjects were collected, but no association between pathological test results and RMD was found.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 726
Keyword
Inborn genetic diseases, Leukoencephalopathies, Lamin type B, Muscular disease, Caveolin 3
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-162048 (URN)978-91-554-8230-5 (ISBN)
Public defence
2012-01-13, Grönwallsalen, Akademiska sjukhuset, Ing 70, Uppsala, 09:15 (English)
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Supervisors
Available from: 2011-12-20 Created: 2011-11-23 Last updated: 2012-01-03Bibliographically approved

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Schuster, JensSundblom, JimmyThuresson, Ann-CharlotteRaininko, RailiMelberg, AtleDahl, Niklas

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