Identification of transcripts from a subtraction library which might be responsible for the mild phenotype in an intrafamilially variable course of Duchenne muscular dystrophy.

Abstract

While frame-shift mutations are usually found in Duchenne muscular dystrophy (DMD), in-frame mutations are associated with the less severe phenotype of Becker's muscular dystrophy. Exceptions have been reported in both directions suggesting the existence of modifying genes, which might be helpful for innovation of new therapeutic strategies. We report on the very rare case of an intrafamilially different course of DMD, with the younger brother being far less affected than the older one when compared at the same age. In this context, we constructed a subtraction library enriched for transcripts over-expressed in the patient with the milder phenotype. Twelve random clones were sequenced, followed by database analysis. Six of them, casein kinase 1 alpha 1, RAP2B, dynactin 3 light chain, core binding factor beta, myosin light polypeptide 2 and one hypothetical gene, were further analysed by real-time RT-PCR. All these genes were over-expressed 3-20 times in the less affected patient compared with the more severely affected one. Casein kinase 1 and the hypothetical gene showed even a slightly higher expression than the control. Up-regulation of myosin light polypeptide 2, one of the most sensitive markers of muscle fibre regeneration, obviously reflects the milder phenotype. Casein kinase 1, dynactin and core binding factor are supposed to be involved in cell cycle pathways. RAP is a component of the signalling network which controls fundamental cellular processes such as proliferation and differentiation. All four might be interesting candidates for a therapeutic approach to diminish progression of dystrophy in DMD.

• Authors: Marco Sifringer, Birgit Uhlenberg, Stefanie Lammel, Rita Hanke, Benjamin Neumann, Arpad von Moers, Ina Koch, Astrid Speer
• Journal: Human genetics (Hum Genet) Vol. 114 Issue 2 Pg. 149-56 (Jan 2004) ISSN: 0340-6717 [Print] Germany
• PMID: 14600829 (Publication Type: Case Reports, Journal Article)

Chemical References

• DCTN3 protein, human
• DNA-Binding Proteins
• Dynactin Complex
• Genetic Markers
• Microtubule-Associated Proteins
• RNA, Messenger
• Transcription Factor AP-2
• Transcription Factors
• Protein Kinases
• Casein Kinases
• RAP2B protein, human
• Myosins
• rap GTP-Binding Proteins

Topics

• Casein Kinases
• Child
• DNA-Binding Proteins (genetics, metabolism)
• Dynactin Complex
• Gene Library
• Genetic Markers
• Humans
• Male
• Microtubule-Associated Proteins (genetics, metabolism)
• Muscle, Skeletal (pathology)
• Muscular Dystrophy, Duchenne (genetics, pathology)
• Mutation
• Myosins (genetics, metabolism)
• Phenotype
• Polymorphism, Genetic
• Protein Kinases (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Subtraction Technique
• Transcription Factor AP-2
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• rap GTP-Binding Proteins (genetics, metabolism)