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Genes and MS susceptibility: a project whose time has come.

Susan, who is 35 and has a three-year-old daughter, has just learned that she has multiple sclerosis. She knows that a distant cousin also has the disease and wonders whether her daughter may develop it

Clifford has had a slowly progressive form Of multiple sclerosis for several years, but he wonders whether it may change to a more rapidly progressive form.

A young man with muscular dystrophy is being treated with a new therapy based on genetic findings in the disease. His neighbor, Cynthia, who has MS, wonders when such a treatment will be available for her.

The names are fictitious, but the questions are real. Answers to these and similar questions depend on the identification of the genetic factors that influence susceptibility to multiple sclerosis. Recent advances in the field known as "molecular genetics," and a new National Multiple Sclerosis Society research project headed by Dr. Stephen Hauser at the Massachusetts General Hospital, using those advances, give hope that doctors will some day be able to answer these questions.

The Background

Heredity Is Important In MS.

Despite many years of research, the cause of multiple sclerosis remains elusive. However, most scientists and physicians who have studied the puzzle of why certain people get the disease while others don't are convinced that heredity-the genes we inherit from our ancestors-is a very important factor.

There are two types of evidence that make scientists think susceptibility to multiple sclerosis depends on the genes a person inherits. The first comes from studies of populations: people from different ethnic groups have different tendencies to develop multiple sclerosis. MS is typically a disease of Caucasians, and many groups of people-Eskimos, African blacks, and Asians-seldom or never develop MS.

The second type of evidence comes from studies of families in which MS occurs more frequently than chance would dictate. The "average" person in the United States has about I chance in 1,000 of developing MS. Close relatives, such as children, siblings or non-identical twins, of people with MS, have a higher chance of developing MS - about 1 in 100 to 1 in 50. Moreover, the identical twin of someone with MS, who shares all the same genes, has about a 1 in 3, or even higher, chance of developing the disease.

These facts tell us genes are important for determining who may get MS, but they are not the whole story: the identical twins of people with MS would always get MS if genes were the only factors involved. So other-perhaps environmental factors -are involved in causing MS, in addition to genes. MS is not directly inherited, but genetic factors may determine who is susceptible to environmental triggers.

In the past few years scientists have developed a set of tools that gives them the ability to pinpoint the genetic factors that make a person susceptible to MS. These tools are the methods of molecular genetics techniques for isolating and determining the chemical structure of genes. In the 1980s scientists began to apply the tools of molecular genetics to human diseases caused by defects in single genes. This work led to major advances in our understanding of such diseases as Duchenne muscular dystrophy and cystic fibrosis, and are leading to attempts to use the basic genetic information to treat the diseases. News stories appear almost daily about advances in knowledge of human genes and genetic diseases.

Genes Are The Recipes Of Life.

Genes, the units of heredity discovered by Gregor Mendel more than a century ago, contain the recipes, or instructions, to make the proteins of which all living things, from bacteria to humans, are built, and that all organisms use to carry out their functions. Because understanding how genes work is basic to the understanding of life and many human diseases, scientists have invested a tremendous amount of time and energy over the past century to learn how they are inherited, what they are made of, how to identify and isolate them, and how to read the coded information contained in them and passed from one generation to the next.

Genes are pieces of a long molecule known as deoxyribonucleic acid, or DNA, and are located along structures called chromosomes in the nuclei - or control centers - of cells in our bodies. The information carried in genes is coded in the sequence of chemical units - called bases - strung together to make DNA, similar to the way information on this page is coded in the sequence of letters on it: each individual letter carries little information, but strung together in the proper sequence they make up words, sentences, and entire books. The genetic "alphabet" has only four "letters" (or bases), and they are arranged in a particular sequence in each gene. The sequence of bases in a gene tells a cell how to make a particular type of protein, just as the sequence of letters in a recipe tells a cook how to make a particular type of food.

Most of the trillions of cells in a person's body have two complete sets of genes - one inherited from the mother, one from the father. Each set contains all the instructions needed to build all human proteins. The collection of all the genes for all human proteins is known as the "human genome"-and numbers about 100,000 genes.

Errors In Genes Can Cause Diseases.

In order for genes to be passed from one generation to another-to be inherited-they must be copied from the parents's genes. The detailed structure of DNA molecules helps insure that accurate copies are made, and the cells that do the copying have "proofreading" mechanisms that correct most copying errors. Like human proofreaders, however, these cellular devices sometimes make mistakes.

Because the genome is copied many times for each generation, there are many slightly different versions of all human genes among the population. Some of this variation is quite harmless, and, indeed, is partly what gives each of us our unique characteristics. Except for identical twins, no two people have the same sequence of DNA bases in their genes. Differences in the DNA sequence are so unique to an individual that DNA analysis can be used for identification in much the way that finger prints are. While variation in genes is normal, sometimes a difference in the code of a gene can be responsible for a disease that can be inherited. Many human diseases are caused by errors in single genes: cystic fibrosis, sickle cell anemia, Duchenne muscular dystrophy, and Huntington's disease are familiar examples. Beginning about ten years ago scientists learned how to identify and isolate the genes for such single-gene diseases, and much progress has been made unraveling the genetic basis of such disorders.

MS Genetics Are More Complex.

The situation for diseases like multiple sclerosis is more complicated, unfortunately. In contrast to single gene diseases where inheritance patterns are relatively simple, the pattern in MS is much more complex. This has led scientists to believe that a person is susceptible to multiple sclerosis only if he or she inherits an unlucky combination of several genes. Until a few years ago, the problem of identifying those genes seemed hopelessly complex. However, advances in molecular genetics, and the identification of large families in which several members have multiple sclerosis-"multiplex" families -have led to the point that the problem is now ready to be attacked.

The Project

Target Of Society Funded Research: MS Susceptibility Genes.

In 1991 the National Multiple Sclerosis Society, through its peer-review committee selected one project, "Genomic search for susceptibility genes in multiple sclerosis," as having the most promising combination of factors needed for success: the scientific expertise necessary to find and identify the genes, and access to a large number of families in which several members have accurately diagnosed, well-documented multiple sclerosis. Not surprisingly, the unique combination of scientific talent and appropriate families was not found through a single institution. Dr. Stephen Hauser will collaborate with Drs. Allen Roses and Margaret Pericak-Vance at Duke University in Chapel Hill, NC, and Dr. Donald Goodkin at the Cleveland Clinic in Cleveland, OH. The project, beginning on April 1st, 1992, and scheduled to run for three years, will cost $576,636.

Hunting For The Needles In The Haystack.

Dr. Hauser and his colleagues have the challenging task of finding an unknown number of genes that confer susceptibility to MS among the 3 trillion DNA bases that code the 100,000 or so genes in the human genome. To do this they will probe the DNA of white blood cells from families where more than one member has multiple sclerosis, looking for identifiable patterns of the DNA code that are inherited in common by the individuals with the disease, but are absent from their healthy relatives.

The investigators have thus far located nearly 80 multiplex families who have agreed to participate in this study, an more are being sought (see box). For this project to succeed, the clinical diagnosis must be absolutely accurate. Incorrect diagnosis, and the resulting inclusion of people who actually don't have MS - and thus lack the genetic code for MS susceptibility that researchers are seeking-could sidetrack the hunt.

In the early stages of this study, the scientists can't look directly at the genes involved in susceptibility to MS, since at this point those genes are unknown. Rather they search for patterns of DNA genetic material that are consistently inherited by people with MS. These recognizable patterns are called "DNA markers." Because of the advances in research on human genetics, scientists now have hundreds of these markers to choose from, located throughout the human genome. Once one of these markers is identified as being consistently inherited by people with MS, the scientists will focus on that area, finding markers closer to the gene, and eventually identifying the absolute location of the gene itself. This process of moving closer to the gene until it is identified will be repeated for each of the marker regions found in the DNA from the multiplex MS families.

What Happens After The Genes Are Located?

After the location of each susceptibility gene is identified, the role that each gene plays in the immunological and neurological aspects of multiple sclerosis will have to be determined. In some cases the role may be relatively easy to determine. Because the immune system is so involved in producing the damage in multiple sclerosis, many scientists think that at least some of the susceptibility genes are related to the immune system. Indeed, there have already been reports linking some immune system genes, such as the T cell receptor, the MHC complex and even immunoglobulin, to multiple sclerosis. However, so far none of these "candidate genes" of the immune system has been linked absolutely to MS. Because Dr. Hauser and his colleagues are looking at all of the human genome, they will be able to pinpoint not only the immune system genes that may be involved in multiple sclerosis susceptibility, but also other genes. They will likely find that previously unidentified genes contribute to multiple sclerosis in ways we cannot currently predict.

What It May Mean To People With MS.

The most important reason for finding the genes that confer susceptibility to multiple sclerosis is that their discovery may lead to the development of new therapeutic approaches and more effective treatments for the disease. The prospect that we will at last be able to get at a basic cause of the disease-an unthinkable possibility only a few years ago-is very exciting. Knowledge of the genetics of multiple sclerosis will provide other benefits.

First, it may help predict the clinical course of the disease in some individuals, making it easier to tailor therapies and providing information to help life decisions. Another possible benefit may lie in early diagnosis of people belonging to families in which one or more member already has multiple sclerosis. Early diagnosis could prove extremely valuable once safe and effective therapies are developed, since many physicians believe that the earlier MS is treated, the better the outcome will be.

In a very real sense, the search for the MS susceptibility genes is a project whose time has come. It could not have been attempted a few years ago-before the techniques to manipulate DNA were developed, before the markers in the human genome were located, and before the computer databases and techniques for analyzing the vast amount of data that such a project will generate became available. And it could not be done without the multiplex families who will provide the raw material to be analyzed. But all the elements are now in place, and the questions posed by Susan, Clifford and Cynthia at the beginning of this article may soon have answers.

Abe Eastwood, Ph.D. Director, Research and Grants Programs

How To Help

Do you or does someone you know belong to a family with more than one member with multiple sclerosis? If so, and if the family members - with and without MS - would be willing to participate in this study, you could help the effort to find the genes responsible for susceptibility to multiple sclerosis. For information about how to help, contact Dr. Stephen Hauser, Neuroimmunology Unit, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114, Tel: (617) 726-3787.
COPYRIGHT 1992 National Multiple Sclerosis Society
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1992, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Title Annotation:multiple sclerosis
Publication:Inside MS
Date:Mar 22, 1992
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