By David N. Leff

Identical twins are not all that identical. For one thing, their fingerprints may vary. For another, observed molecular geneticist Laura Ranum, ¿two monozygotic twins aged 31, both afflicted with myotonic dystrophy, had surprisingly differing repeat sizes in their DNA ¿ typically thought to have been identical.¿

Ranum, at the University of Minnesota in Minneapolis, analyzed the pair¿s genomes, and discovered they had ¿dramatically different expanded alleles [parental gene variants] ¿ one 13,000 base pairs long, the other 24,000.

¿This is the largest microsatellite repeat expansion found to date,¿ she pointed out. ¿The nucleotide iterations increased with the age of the twin patients. One affected individual¿s lymphocyte DNA expanded in size by approximately 2,000 bases during the three-year interval between our two blood samplings.¿

Ranum is an associate professor of genetics, cell biology and development at the university¿s Institute of Genetics. Today¿s issue of Science, dated August 3, 2001, carries a research article of which she is senior author. Its title: ¿Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9 [zinc finger gene].¿

Neurodegenerative diseases such as Huntington¿s and spinocerebellar ataxia feature triple-codon DNA repeats. Myotonic dystrophy type 2, as reported in Science, raises that ante to quadruplets ¿ CCTG ¿ standing for cytosine-cytosine-thymine-guanine nucleotides.

Multi-Organ Ills From Cataracts To Diabetes

¿We report having found a mutation that causes the second form of myotonic dystrophy,¿ Ranum told BioWorld Today. ¿Our findings have implications for better understanding both types 1 and 2 of the disease. Type 2,¿ she continued, ¿is a gigantic CCTG repeat expansion that¿s present in an intron ¿ a noncoding stretch of a gene sequence. And we have demonstrated that the transcript that¿s made from that gene accumulates in nuclei as RNA foci. What I think is particularly informative,¿ Ranum suggested, ¿is that the type 2 disease we¿re studying is very, very similar to myotonic dystrophy type 1. It has a really unusual constellation of clinical features that are found in both diseases.

¿There are cataracts with red and green opacities,¿ she recounted. ¿There are cardiac arrhythmias, myotonia ¿ the inability to relax muscles, a particular pathology associated with the muscle ¿ hormonal dysfunction, premature frontal baldness. There are these RNA inclusions in the cell nuclei, and it¿s been controversial for some time what has caused this spectrum of clinical features in myotonic dystrophy. We think our finding indicates that RNA ¿ the repeat expansions in RNA themselves ¿ play a larger role in myotonic dystrophy than had previously been thought. That these were responsible for the multisystemic features of both diseases.¿

¿Muscular dystrophy was described nearly a century ago,¿ the Science paper recalled, ¿but the existence of more than one genetic cause was only recognized after genetic testing became available for myotonic dystrophy type 1.¿

Scientists found the genetic changes underlying type 1 myotonic dystrophy on the long arm of human chromosome 19 in 1992. They¿ve been arguing ever since as to how a noncoding portion of a gene causes disease. ¿There¿s been a substantial amount of work in type 1 myotonic dystrophy,¿ Ranum recalled, ¿to begin to unravel that puzzle. It¿s been shown by a number of investigators that the RNA expansions themselves bind to other proteins. And those proteins are important in gene regulation ¿ particularly splicing of other genes. So these RNA expansions were thought to play a role in myotonic dystrophy, and have been for a number of years now.

¿But they weren¿t thought to be responsible for the whole picture,¿ she added. ¿And now we think that the major parallel between myotonic dystrophy type 1 and type 2 is that there¿s an expansion in RNA that accumulates in the nucleus, and therefore that¿s the primary mechanism. That RNA is directly involved in the disease process. RNA is the messenger molecule that translates the DNA code into proteins,¿ she pointed out. ¿In the past, the focus has been on protein abnormalities as the cause of genetic disorders, and researchers thought that RNA had little or no direct role in causing diseases.¿

Ranum and her co-authors located the genetic basis of myotonic dystrophy type 2 in 1998 on chromosome 3. They collaborated with scientists in Germany and Texas to find the underlying gene mutation. Their current report in Science indicates that the abnormal pile-up of RNA causes both types.

Myotonic dystrophy afflicts mostly adults of both sexes. It¿s the commonest adult muscle-wasting disease, and currently affects some 40,000 patients in the U.S. It¿s usually diagnosed in adults between 30 and 50 years of age. By comparison, Duchenne dystrophy attacks one in 3,000 male babies born in the U.S. (See BioWorld Today, Sept. 8, 2000, p. 1.)

Immediate Payoffs For Families: Diagnosis

Type 2 myotonic dystrophy is quite common in Germany and in Minnesota families, many of whose members are of German ancestry. Ranum and her co-authors analyzed the clinical and genetic features of nearly 200 individuals ¿ including those identical twins ¿ from 100 families with type 2.

¿I think there are some diagnostic implications for families immediately,¿ Ranum allowed. ¿These findings will help to better diagnose patients. Myotonic dystrophy can result in a number of very serious health problems, including diabetes and cardiac arrhythmias. By being able to detect this type of the disease earlier ¿ and especially because its milder form can be missed ¿ proper diagnosis is important in managing the disease. And long term,¿ she went on, ¿we hope that it will focus research, and speed things along, to get a handle on this disease, and eventually develop some effective treatments. As we learn more about its specific effects, we would wish to be able to intervene therapeutically.¿

Co-author John Day seconded this observation: ¿These results enable us to focus our research and to work toward eliminating this disease for future generations of families. But perhaps more importantly, for the first time there is indisputable evidence that RNA itself can cause disease.¿

Ranum and her lab are now trying to develop a mouse model for myotonic dystrophy type 2, ¿one that has the multisystem features of the disease. That work is in progress,¿ she concluded.

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