title: Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.
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.
authors.affiliation: Department of Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University and University Hospital, SE-751 85, Uppsala, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Schuster
authors.forename: Jimmy
authors.initials: J
authors.lastname: Sundblom
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.forename: Sharon
authors.initials: S
authors.lastname: Hassin-Baer
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Oren S
authors.initials: OS
authors.lastname: Cohen
authors.forename: Raili
authors.initials: R
authors.lastname: Raininko
authors.forename: Atle
authors.initials: A
authors.lastname: Melberg
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000328:Adult; D001342:Autonomic Nervous System Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D015870:Gene Expression; D005799:Genes, Dominant; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D006801:Humans; D034921:Lamin Type B / Q000097:blood / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics
chemical_list: D034921:Lamin Type B; D012333:RNA, Messenger