Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
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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.
KeywordsLMNB1 Duplication Autosomal dominant leukodystrophy (ADLD) Autonomic symptoms Lamin B1
Autosomal dominant leukodystrophy
Copy number variation
Single nucleotide polymorphism
Polymerase chain reaction
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.
The study was approved by the local Ethics Committee of Uppsala University Hospital and individuals who entered the study gave oral and written consent.
The authors report no financial competing interests
Conflict of interest
The authors report no conflict of interest
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