By David N. Leff
Tracking down and dealing with Osama bin Laden is proving to be a tricky and fraught undertaking. A different kind of search, but one that also involves Muslim populations, is the hunt for genes hidden in the blood of four families ¿ two from Tunisia, two from Saudi Arabia.
These genetic targets do their mayhem and mortality on a smaller scale than terrorists. They perpetrate ALS ¿ amyotrophic lateral sclerosis ¿ better known as Lou Gehrig¿s disease. A celebrated survivor is British theoretical physicist Stephen Hawking, who contracted ALS in his mid-20s some 40 years ago, and amazingly overcomes its disabilities.
¿ALS is a terminal, progressive neuromuscular malady,¿ observed clinical neurobiologist Teepu Siddique, at Northwestern University in Chicago. ¿It renders the muscles of the body useless, while leaving the mind unimpaired. There is currently no effective treatment for ALS. It¿s a neurodegenerative disease of the brain¿s motor system. That is,¿ he continued, ¿the upper motor neuron, which goes from the brain¿s cerebral cortex down to the brain stem and then on down to the spinal cord, is affected. The patient ends up with spastic paralysis ¿ movement difficulty.¿
But this grim picture has a milder side. ALS, itself a rare disease, has an even rarer, less severe look-alike affliction called PLS ¿ primary lateral sclerosis. It trashes only the motor neurons in the cerebral cortex.
¿But in ALS,¿ Siddique pointed out, ¿the final common pathway that starts from the lower motor neuron, which is the large motor neuron in the brain stem and the spinal cord, degenerates, with muscle atrophy and severe weakness. So ALS is a much more severe disease. And that is the difference between ALS and PLS.¿
Siddique, who holds an endowed chair of neurology and cell biology at Northwestern, is senior author of a paper in the October issue of Nature Genetics, released today, Oct. 3, 2001. Its title: ¿The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.¿ Among its international consortium of 17 co-authors are two from hospitals in Saudi Arabia and one from Tunisia.
True Amyotrophic Lateral Sclerosis Cause?
¿The significance of this article,¿ Siddique told BioWorld Today, ¿is that there¿s only one other known cause of ALS, which is what we had described in ¿93 as mutations in the gene for SOD ¿ superoxide dismutase. This is the second known cause. There are a lot of theories and hypotheses to date, but none of them really adds up to a cause.
¿What we report,¿ he continued, ¿is a kind of ALS that is slow. Stephen Hawking has a slowly progressing variety of ALS. And we address that variety, in which symptoms start at age 4 and usually progress into the 20s. The third point we present is primary lateral sclerosis. People have debated the nature of PLS, asking whether it¿s a separate disease, or a form of ALS. We show in this paper that both kinds of clinical condition can be caused by different mutations, but mutations in the same gene.
¿Our first experiment,¿ Siddique recounted, ¿was to find where the gene was located. That is now the classical approach of positional cloning ¿ you first do genetic linkage, which is what we did, analyzing a large Tunisian family. And then, because it was a single family, at that time, we didn¿t know where the gene was in this huge genomic region of 10 megabases of DNA. At that time there wasn¿t the Human Genome Project.
¿So we made a library of that region, and showed that actually the gene was confined to a narrow band. Once we knew its margins, that substantially reduced the distance. Eventually we ended up with distance of 1.65 megabases, and then identified the gene on the long arm of human chromosome 2.
¿By this time,¿ Siddique recalled, ¿the Human Genome Project was afoot, and the last year or so more and more genes were identified, or predicted, in this region. So we started sequencing exons that were either there or predicted. And after a lot of sequencing, we were able to find this particular gene that had these mutations in the two Saudi and two Tunisian families.¿
He went on: ¿The newly identified gene mutation is responsible for a rare, slowly progressive, early onset, somatic-recessive form of the disease, called juvenile inherited ALS2,¿ discovered in highly inbred populations in North Africa and the Middle East. Its symptoms manifest in the first or second decade of life, and progress slowly for 10 or 15 years. In patients with the better-known autosomal dominant ALS, symptoms usually occur at age 40 to 50, and patients die within five years.¿ (See BioWorld Today, Nov. 14, 2000, p. 1.)
Marrying Close Relatives Raises ALS Ante
¿We had genetically linked one very large Tunisian family back in 1994,¿ Siddique recalled. ¿And because of consanguinity ¿ first-cousin marriage ¿ we were able to obtain such families in which there is the recessive rare PLS. In outbred populations, such as here in the U.S.,¿ he pointed out, ¿the chances of finding such families are very small. But if people with PLS appear sporadically, or out of the blue, we can test them to see if they have mutations in the same gene.¿
Siddique made the point, ¿Both of these disorders ¿ ALS and PLS ¿ are very rare. But their importance is not in the public health sense. Rather, it is in the sense of understanding the mechanism by which motor neurons degenerate. Here we have this rare experiment of nature, and that helps us to understand how redundant pathways in nature may be affected to produce such a disease.
¿So I think that has direct relevance in understanding motor neuron degeneration, and perhaps degeneration of another kind. Because one of the nucleotide motifs we saw is also present in a gene that causes retinal degeneration ¿ retinitis pigmentosa. So this may be a common pathway in degeneration both of sensory and of motor systems, and that may be a bedrock issue related to overall neurodegeneration.
¿I think the most important thing,¿ Siddique concluded, ¿is that this should allow us to find a biochemical pathway which may be strategic for therapeutic intervention.¿