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PubMed1994

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

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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PubMed2004

Concerns about the design of clinical trials for spinal muscular atrophy.

The distinctive clinical course of SMA, characterized by slowing of the rate of degeneration with the passage of time, presents a special challenge to therapeutic clinical trial planning. Much of the actual functional decline may represent either an inevitable consequence of growth or the result of various secondary complications of weakness, making the study of agents intended to improve the course by increasing the level of SMN protein that much more difficult. Studies intended to demonstrate a slowing of the rate of degeneration, modeled upon clinical trials for ALS, are problematic. In contrast, short-term trials designed to demonstrate improved strength have substantial design advantages, but depend upon the demonstration of salutary effects of increased SMN that are plausible but at present only theoretical. This form of study thus has some potential for type II error, falsely rejecting a useful drug. Despite this limitation, logistic and statistical concerns suggest that the best strategy for evaluating any promising new therapy will be to use first a short-term study.

Animals↗
PubMed1996

Exclusion of the beta-subunit of type II calmodulin kinase for the wobbler spinal muscular atrophy gene.

The wobbler mouse (wr) is an attractive model for studying motor neuron disease but the genetic defect is unknown. The beta-subunit of calmodulin kinase II (beta-CaMK II) is a good candidate for the wr mutation because of its chromosomal localization and tissue distribution. In this report, we found normal levels of CaM KII mRNA and enzyme activity making it highly unlikely that a mutation in the beta-CaM KII gene is the cause of the wr phenotype.

Animals↗