Motor neuron diseases like amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are typified by the degeneration of alpha motor neurons in the spinal cord that subsequently leads to muscle atrophy. The nature of such neuromuscular disorders appears to be complex but spontaneous mouse mutants are helping to pinpoint critical genetic variables. The mouse neuromuscular degeneration nmd mutant mice express an autosomal recessive neurological disease where motor neurons degenerate causing the skeletal muscle fibers to atrophy. Behaviorally, these mice are easily identifiable by the second postnatal week. The hindlimbs are dorsally contracted and their locomotor activity is impaired, but balance is not adversely affected. They cannot extend their legs to stand erect or assume full posture on all four limbs. Homozygotes clench their hindlimbs when picked up by the tail and they are unable to grasp a cage cover when held against it. They can maintain proper balance, however, and do not circle, bob their heads, or fall over sideways. Paralysis usually begins in the hindlimbs and later develops in the forelimbs as the disease progresses. Most homozygous mutants die by 3.5-4 weeks of age. Heterozygotes are phenotypically and histologically normal.
The mutant phenotype is very similar to that seen in the human diseases ALS and SMA. The pathology displayed by the degenerating neurons in both species appears similar in that the affected cells seem to "fade away", or stain more lightly for hematoxylin and eosin (H&E) and luxol fast blue-cresylecht violet (LFB-CV). The "fading away" neurons are not swollen, rather the cytoplasmic and nuclear organelles, while normal in structure, appear less densely packed. The populations of motor neurons that are most highly affected by the mouse nmd alleles are those found in the lumbar region, whereas the neurons in the thoracic and cervical spinal cord regions appear primarily normal. Degenerating alpha motor neurons are also found in the sympathetic chain. The muscle fiber lesions contain a mixture of tiny muscle fibers and normally sized fibers. Compared to the proximal muscle groups, the distal musculature of the forelimbs and hindlimbs contain more severe atrophic lesions with adipose tissue abnormally appearing in some instances. The pathology appears limited to neuromuscular aspects since inflammatory and gliotic responses to the lesions are not detected. The overall pattern of muscle denervation and atrophy appears to be random. Finally, it is not clear why the motor neurons are selectively sensitive to the significantly reduced levels of IGHMBP2 given that this DNA binding protein is widely expressed across many cell types. DNA sequencing reveals the (nmd-2J) mutation has a single A to G transition in intron 4 which results in a cryptic splice donor (interfering with the normal transcript splicing) and produces an abnormally spliced transcript with an additional 23bp and a premature stop codon. RT-PCR analysis of various tissues, including brain and spinal cord, shows that the abnormal mutant splicing produces 20-25% wildtype splicing and 75-80% mutant splicing. (Cook et al., 1995; Cox et al., 1998; Schmalbruch et al., 1991; Grohmann et al., 2001; Mizuta et al., 1993; Chen et al., 1997; Zhang et al., 1999).
