GENETICS OF MOTOR NEURONE DISEASE

 

 

Motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of unknown cause pathologically characterised by progressive degeneration of motor neurones in the cortex, brain stem and spinal cord. It is mainly sporadic, however 5-10% of MND/ALS cases are familial. In these cases, the clinical and pathological features are indistinguishable from those in the sporadic form of the disease. Furthermore, a number of inherited conditions, clinically and pathologically related to classical MND/ALS, exist. Thus, much effort has been dedicated to the identification of the genetic abnormalities involved in motor neurone degeneration. Elucidation of the molecular basis of motor neurone death would, in fact, provide targets for therapy. To date, mutations leading to motor neurone degeneration have been found in:

1) the superoxide dismutase (SOD 1) gene in chromosome 21 -linked  /1 MND/ALS families

2) the neurofilament heavy (NF-H) gene_In sporadic MND/ALS,

3) the_androgen receptor gene in X-linked bulbospinal neuronopathy (SBMA or Kennedy's disease).

 

SODI gene mutations in familial MND/ALS

 

Familial MND/ALS, clinically indistinguishable from sporadic MND/ALS, is expressed as an age-dependent autosomal dominant trait. In a subset of MND/ALS families, genetic linkage has recently been established with markers on chromosome 2 1q22. 1. In these families, SOD 1, the gene encoding the cytosolic antioxidant enzyme Cu, Zn superoxide dismutase (SOD) has subsequently been studied as a candidate gene because of its proximity to the familial MND/ALS locus.

 

Genomic DNA from members of the chromosome 21-linked MND/ALS families and normal controls has been amplified by the polymerase chain reaction (PCR) and examined for single-stranded conformation polymorphism (SSCP), by changes in DNA migration on nondenaturing polyacrylamide gels. In 30% of the chromosome 21 -linkcd families, this approach has led to the identification of 14

 

point mutations in exons 1,2,4 and 5 of the SODi gene. No changes in the sequence have been found in exon 3 or In genomic DNA from normal individuals.

 

Although no mutations have been found in the SOD 1 gene in sporadic MND/ALS, biochemical studies have now provided evidence of increased oxidative damage to proteins also in these cases.

 

Superoxide dismutase is involved in the removal of free radicals normally produccd in cellular metabolism. All the mutations described in familial MND/ALS code for amino acid residues which disrupt the normal three­ dimensional structure of the enzyme. Therefore,  this discovery suggests free radical toxicity as the primary pathogenic mechanism for motor neurone death in familial MND/ALS. Studies are now being carried out to establish the functional consequences of the gene mutations as well as the involvement of  sporadic MND/ALS oxidative damage in the pathogenesis of familial a

 

 

Neurofilament heavy (NF-H) gene mutations in sporadic MND/ALS

 

 

A direct role of neurofilament in the pathogeneis  of MND/ALS has been suggested by the abnormal accumulations of neurofilaments which are one of the pathological hallmarks of MND/ALS. Furthermore, transgenic mice models have shown that overexpression of neurofilament subunits leads to motor neurone dysfunction. The NF-H protein includes a unique phosphorylation domain of multiple lysine-serine-proline (KSP) repeats located in the side-arms, appearing to modulate the spacing between neurofilaments. The liumm NF-H sequence contains 43 KSP repeats. However, an NF-H allelic variant containing 44 KSP repeats has been identified. The distribution of the 43 and 44 NF-H allelic variants has been examined in DNA samples from 148 control individuals and 273 non related individuals with sporadic MND/ALS. The allelic distribution between the two groups varies significantly. Moreover, in 3 MND/ALS patients, mutations have been found in the phosphorviation domain of NF-H. One MND/ALS patient has a 102 bp deletion, which includes 5 KSP repeats, while two other MND/ALS patients have a mutant NF-H allele with Q3 bp deletion including a lysine residue. These mutations may alter the cross-linking properties of NF-H, therefore resulting in an impairment of neurofilament transport.

 

 

 

Androgen receptor gene mutations in Kennedy's disease

 

X-_linked spinal and bulbar muscular atro rophy or Kennedy's disease is a recessive,

adult-onset form of lower motor neurone degeneration also associated with signs of androgen insensitivity. The androgen receptor gene has been mapped to chromosome Xq 11 - 12, where linkage studies have localysed the SBMA gene defect. The first exon of the gene contains a polymorphic CAG repeat, coding_for a polyglutamine strech. The number of the CAG repeats normally varies In the population between 15 to 33. However, In Kennedy's disease patients, the number of the repeats varies from 40 to 52. There is an absolute association of the larger polyglutamine stretch with the disease phenotype and, furthermore, the number of the repeats correlates with the severity of the disease. This is the only known mutation of the androgen receptor gene associated with motor neurone degeneration. Functional studies of the receptor carrying the expanded polyglutamine stretch have now shown that the mutated protein exhibits reduced transcriptional competence, The molecular mechanisms by which this may impair motor neuron-specific survival remain to be clarified.

 

 

Conclusions

 

The specific genetic lesions which, so far, have been identified in classical sporadic and familial MND /ALS, as well as the related condition Kennedy's disease, point to a wide range of causes underlying motor neurone degeneration. The functional effects of these various genetic abnormalities need to be fully Investigated, in order to identify putative targets for therapy.