Elsevier

Progress in Neurobiology

Volume 42, Issue 2, February 1994, Pages 313-317
Progress in Neurobiology

Exploring the mammalian neuromuscular system by analysis of mutations: Spinal muscular atrophy and myotonia

https://doi.org/10.1016/0301-0082(94)90071-XGet rights and content

Abstract

Any biological structure can be studied using mutations that interfere either with its emergence or its function. We investigate spontaneous and induced mutations in the mouse that affect neuromuscular development and function. The wobbler mouse (phenotype WR, genotype wr/wr) suffers from muscular atrophy because of the degeneration of 20–40% of the motoneurones; it is also unable to produce functional spermatozoa. As a step towards positional cloning of the wr gene, we have mapped the locus to proximal chromosome 11, thus excluding CNTF and its receptor as candidates, and suggesting the closely-linked Rab 1 gene encoding a GTP-binding protein as a possibility. In the case of the adr (arrested development of righting response) mouse, which shows hyperexcitability of mature muscle fibres due to a reduction of the ‘dampening’ function of chloride conductance at resting potential, we have shown that the defect is in the chloride channel gene adr/Clc-1 on chromosome 6. This allowed us to predict via synteny the chromosomal location of human Thomsen's and Becker's myotonias as close to the TCRB gene on human chromosome 7q. The combination of these approaches with gene-targeting approaches will allow genetic analysis of the establishment and structure of the neuromuscular system.

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      As a referee of our SFB he used to say: “The ADR mouse is a wonderful model of our stimulation experiments,” but my version was “Dirk Pette's stimulation experiments provide a nice model of myotonic muscle.” Not only does myotonia influence, via the excitation pattern, mRNA levels of myogenic factors and, probably indirectly, levels of all proteins characteristic for muscle fiber type [50,52,69,70], but also the level of ClC-1 mRNA and thereby by the function of its own protein product [71], leading to a closed loop of relation between excitability and gene expression in muscle [72] (Figure 7, lower part). Interestingly, there is a post-transcriptional dosage compensation, ensuring that the sarcolemmal chloride conductance is equal (and typical for the fiber type) whether there is a full dosage of ClC-1 mRNA (as in the homozygous wild type) or half the concentration as in heterozygous +/adr animals [73].

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