Molecular characterization of the genetic lesion in Dystonia musculorum (dt-Alb) mice
pmid: 16725123
Molecular characterization of the genetic lesion in Dystonia musculorum (dt-Alb) mice
Dystonia musculorum (dt) is an inherited autosomal recessive neuropathy in mice. Homozygous animals display primarily sensory neurodegeneration resulting in a severe loss of coordination. Several dt strains exist, including spontaneous mutants dt-Alb (Albany), dt-J (Jackson Labs), and dt-Frk (Frankel), and a transgene insertion mutant, Tg4. They contain mutations in the gene encoding Bullous Pemphigoid Antigen 1 (BPAG1), or dystonin. BPAG1 is a member of the plakin family of cytolinker proteins. BPAG1 is alternatively spliced to produce several isoforms, including the major brain-specific isoform, BPAG1a. The neurological phenotype observed in dt-Alb mice is thought to result from the absence of BPAG1a protein in the developing nervous system. The goal of this study was to determine the precise molecular nature of the dt-Alb mutation and examine residual BPAG1 expression in homozygous dt-Alb mice. A combination of molecular biological strategies revealed that the dt-Alb lesion is a deletion-insertion eliminating a large part of the coding region of BPAG1a. The molecular lesion in the dt-Alb BPAG1 allele is expected to render it completely non-functional. Although transcripts corresponding to BPAG1 segments still remaining in homozygous dt-Alb mice could be detected by RT-PCR, there was no positive signal for BPAG1 in the brain of dt-Alb mice by Northern blotting. Western blotting with polyclonal anti-BPAG1 antibodies confirmed the absence of functional BPAG1 protein (full-length or truncated) in the dt-Alb brain. Our identification of the 5' junction of the dt-Alb insertion makes it possible to genotype dt-Alb animals by standard PCR.
- Columbia University United States
- Wadsworth Center United States
- New York State Department of Health United States
- University Physicians United States
Genotype, Dystonin, Reverse Transcriptase Polymerase Chain Reaction, Brain, Gene Expression, Mice, Transgenic, Nerve Tissue Proteins, Cytoskeletal Proteins, Mice, Mice, Neurologic Mutants, Phenotype, Mutation, Animals, RNA, Messenger, Carrier Proteins, Molecular Biology
Genotype, Dystonin, Reverse Transcriptase Polymerase Chain Reaction, Brain, Gene Expression, Mice, Transgenic, Nerve Tissue Proteins, Cytoskeletal Proteins, Mice, Mice, Neurologic Mutants, Phenotype, Mutation, Animals, RNA, Messenger, Carrier Proteins, Molecular Biology
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