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neurogenetics

, Volume 12, Issue 1, pp 65–72 | Cite as

Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms

  • Jens Schuster
  • Jimmy Sundblom
  • Ann-Charlotte Thuresson
  • Sharon Hassin-Baer
  • Thomas Klopstock
  • Martin Dichgans
  • Oren S. Cohen
  • Raili Raininko
  • Atle Melberg
  • Niklas Dahl
ORIGINAL ARTICLE

Abstract

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.

Keywords

LMNB1 Duplication Autosomal dominant leukodystrophy (ADLD) Autonomic symptoms Lamin B1 

Abbreviation

ADLD

Autosomal dominant leukodystrophy

CNV

Copy number variation

MR

Magnetic resonance

SNP

Single nucleotide polymorphism

PCR

Polymerase chain reaction

Notes

Acknowledgments

We thank the patients and families who participated in this study. This project was financially supported by the Swedish Research Council, the Sävstaholm Society, Hedberg foundation for Medical Research, Selander Foundation, the Swedish Association for the Neurologically Disabled, Uppsala University and Uppsala University Hospital.

Ethical standards

The study was approved by the local Ethics Committee of Uppsala University Hospital and individuals who entered the study gave oral and written consent.

Financial disclosure

The authors report no financial competing interests

Conflict of interest

The authors report no conflict of interest

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jens Schuster
    • 1
  • Jimmy Sundblom
    • 2
  • Ann-Charlotte Thuresson
    • 1
  • Sharon Hassin-Baer
    • 3
    • 4
  • Thomas Klopstock
    • 5
  • Martin Dichgans
    • 6
  • Oren S. Cohen
    • 3
  • Raili Raininko
    • 7
  • Atle Melberg
    • 2
  • Niklas Dahl
    • 1
  1. 1.Department of Genetics and Pathology, The Rudbeck Laboratory and Science for Life LaboratoryUppsala University and University HospitalUppsalaSweden
  2. 2.Department of Neuroscience, NeurologyUppsala University and University HospitalUppsalaSweden
  3. 3.Department of Neurology and Parkinson’s Disease and Movement Disorders Clinic, Sagol Neuroscience CenterChaim Sheba Medical CenterTel HashomerIsrael
  4. 4.The Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  5. 5.Friedrich Baur Institute, Department of NeurologyLudwig Maximilians UniversityMunichGermany
  6. 6.Department of Neurology, Neurologische Klinik, Klinikum GrosshadernLudwig Maximilians UniversityMunichGermany
  7. 7.Department of RadiologyUppsala University and University HospitalUppsalaSweden

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