Establishing the connection between a mutation and a clinical problem is in itself not easy. More difficult still is to prove the connection between a genetic alteration and more than one pathology. In a work published in September in the electronic edition of the American Journal of Human Genetics magazine, researchers from the University of São Paulo (USP) show that a mutation in the VAP-B gene, present in human chromosome 20, can cause three different kinds of degenerative diseases in the motor neurons: progressive or late onset spinal muscular atrophy, amyotrophic lateral sclerosis (ALS), and one of the atypical forms of amyotrophic lateral sclerosis, ALS8.
The dysfunction in the gene was found in 34 individuals, belonging to seven families: 16 people had spinal atrophy, 15 were showing ALS8, and three manifested the classic form of ALS. “We do not yet know why the mutation causes different pathologies”, explains geneticist Mayana Zatz, the coordinator of the researches that led to the scientific article and of USP’s Human Genome Studies Center, one of the ten Research, Innovation and Diffusion Centers (Cepids) financed by FAPESP. “It is possible that other genes may have a protecting or aggravating action in relation to the effect of the alteration in the VAP-B”, says Agnes Nishimura, who is studying for a doctorate and is the main author of the article.
The three diseases are similar and, in certain aspects, blend into each other. The similarity may perhaps be due to the discovery that the mutation in the VAP-B gene may be the cause of the anomalies. In a generic way, they are classified under the large umbrella of the so-called motor neuron diseases. They are lesions that affect the cells of the brain and/or of the spinal cord specialized in sending electric impulses to the muscles. These contract or relax following commands transmitted by the upper (brain) or lower (spinal cord) motor neurons. If this group of cells degenerates, as happens on a greater or lesser scale in the three diseases, the muscles become weak and stiff.
Neurons and muscles do not talk to each other any more. According to the location and the speed of progression of the lesion, the patients lose the capacity for moving parts of the body. With time, some may even lose the mastery of their voice and the capacity for chewing food. The difficulty in breathing without the help of a device, in general, the cause of death. The senses of touch, smell, sight, taste and hearing are not usually affected by the diseases. Intellectual capability is also preserved. The best proof of this is the English physicist, Stephen Hawking, who suffers from an atypical form of ALS.
In the traditional form of ALS, the most common of the three diseases, the lesions affect nerve cells of the brain and of the spinal cord, and the pains and limitations in movement tend to become generalized over the victim’s body. The maximum time of life for the patient after the appearance of the first symptoms, usually after the age of 40, is from two to five years. About 90% of the classic cases in the USA are not hereditary. The other 10% run in the family, like those that were the object of the work of the Brazilian researchers: they can pass from parents to children.
Besides the mutation now found in the VAP-B, alterations in another three genes are apparently linked to the disease. Although as equally fatal as the classic ALS, the atypical form of amyotrophic lateral sclerosis studied at USP, the ALS8, develops in a far slower way. “The patients live with the disease for decades”, says biologist Miguel Mitne-Neto, another author of the study that found the mutation in the VAP-B gene. Progressive spinal atrophy of late onset is exclusively a result of lesions in the motor neurons responsible for the innervation of the muscles. The infantile form is relatively common. The late onset kind, very rare. The symptoms appear around the age of 50 years old, and its evolution is sluggish. Like ALS8, spinal atrophy is hereditary.
Finding the genetic alteration was a two year work. The researchers did clinical and DNA examinations in dozens of people from the seven families with members affected by the diseases, who were to be found scattered over the states of Minas Gerais, Rio de Janeiro, the Federal District and São Paulo. Some patients turned spontaneously to the Human Genome Studies Center, known for carrying out work with degenerative syndromes. “I saw an article in the paper about the center and I went to São Paulo”, comments Lecy Gonçalves de Souza, 62 years old, an inhabitant of Niterói, Rio de Janeiro, who has had ALS8 for almost three decades.
The scientists also tried to reconstitute the genealogical tree of each one of the clans, and also to establish a possible relationship of kinship. Although it was not possible to prove the biological link between all the families, the history of these individuals seems to point to the existence of a common ancestor, or Portuguese origin, who lived in territory of the state of Minas Gerais over a century ago. “Our information indicates that, in the course of eight generations, these families have had 1,300 healthy persons and over 200 cases of neurodegenerative diseases”, comments Mayana.
The VAP-B gene controls the production of a homonymous protein involved in the transport of substance in the inside of cells. If a target for a mutation, it must induce the synthesis of abnormal forms of the protein. The team from USP suspects that the altered versions of the VAP-B may build up inside the cells, as if they were micronodules, and can lead to the death of motor neurons. The idea is still a hypothesis, but it is supported by experiments done with human and mouse tissue by Paul Skehel, from the University of Edinburgh, Scotland, a collaborator of the USP team. Besides man, the gene is present in other organisms, like flies, rodents and yeasts. This particularity should assist in the search for more data about the biological mechanisms that prompt the neuromuscular disturbances. “Our British colleagues want to make transgenic mice to act as a model for the diseases”, says Agnes. Researchers from the University of California at Los Angeles, who are collaborating with the Brazilians, want to do thesame with the fruit fly (Drosophila melanogaster).
Human Genome Studies Center; Modality Research, Innovation and Diffusion Centers (Cepid); Coordinator Mayana Zatz – USP; Investment R$ 1,000,000.00 per annum