Laura Ranum, Ph.D.

Professor, Ph.D. University of Minnesota, 1989
Institute of Human Genetics
Dept. of Genetics, Cell Biology and Development
6-160 Jackson Hall
321 Church St. S.E.
Minneapolis, MN 55455
Office: 5-128 MCB
Phone: (612) 624-0901
Lab: 5-162 MCB
Phone: (612) 626-3521
Fax: (612) 625-8488
e-mail: ranum001@umn.edu

Areas of Research Strength:

Research Techniques Used:

Human genetics, genetic mapping, positional cloning, transgenic models

Research Interests:

Many neurodegenerative diseases begin later in life after the nervous system is fully developed. The biochemical bases for the initiation of the degenerative processes are not understood. A major step towards a better understanding of neurodegenerative diseases was made with the discovery that microsatellite repeat expansions are responsible for a number of these diseases. Our group is interested in understanding how repeat expansions cause myotonic dystrophy and ataxia.

Myotonic dystrophy (DM) is a multisystemic disease and the most common form of muscular dystrophy in adults. In 1992, DM was shown to be caused by an expanded CTG repeat in the 3' untranslated region of the myotonin protein kinase gene (DMPK) on chromosome 19. Although several theories have been proposed to explain how the CTG expansion causes the broad spectrum of clinical features associated with DM, it has not been understood how this mutation, which does not alter the protein coding region of a gene, causes an effect at the cellular level. We have identified a five-generation family (MN1) with a genetically distinct form of myotonic dystrophy. Affected members exhibit remarkable clinical similarity to DM (myotonia, proximal and distal limb weakness, frontal balding, cataracts and cardiac arrhythmias) but do not have the chromosome 19 CTG expansion. We mapped the disease locus (DM2) for the MN1 family to a 10 cM region of chromosome 3q. We used positional cloning and linkage disequilibrium strategies to isolate the gene and demonstrated that the disease is caused by a CCTG tetranucleotide expansion in intron 1 of the zinc finger protein 9 gene. Similar to the DM1 CUG repeat, RNA containing the expanded DM2 CCUG repeat tract accumulate in muscle nuclei (Photo). Molecular parallels between DM1 and DM2 indicate that expansions in RNA can themselves be pathogenic and cause the multisystemic features common to both diseases (Science, 293:864-867). Future directions include generating a murine model to better understand the disease process.

Another area of our research is directed towards understanding the molecular causes of ataxia. The ataxias are a group of neurodegenerative diseases that to varying degrees affect the cerebellum, brainstem, and spinocerebellar tracts. Patients lose their ability to coordinate movements causing difficulty with gait, speech and swallowing. We have collected DNA samples from patients representing 400 different ataxia kindreds with dominant, recessive, or sporadic forms of adult-onset ataxia. Among the 178 dominant kindreds represented, the ataxia for approximately 60% of the families is caused by a CAG trinucleotide repeat expansion in one of the five ataxia genes that have been identified to date. In general these CAG expansions are translated into polyglutamine tracts in the corresponding proteins. To speed the identification of additional ataxia genes we developed a novel method to clone potentially pathogenic trinucleotide repeat expansions from the genomic DNA of single affected individuals. Using our method of repeat analysis pooled isolation and detection (RAPID) cloning we recently isolated two novel ataxia genes for spinocerebellar ataxia types 7 and 8 (SCA7 & SCA8).

The inheritance pattern of SCA8, though generally dominant, is complicated, showing reduced penetrance and a strong maternal penetrance bias. Surprisingly, molecular analyses of this expansion revealed that, unlike the other SCA CAG mutations characterized to date, the SCA8 expansion is not translated as a polyglutamine tract. Rather, the expanded repeat is an untranslated CTG expansion near the 3' end of a naturally occurring antisense transcript. Myotonic dystrophy is the only other disease known to be caused by an untranslated CTG expansion.

SCA8 has the clinical features typical of spinocerebellar ataxia, whereas the untranslated CTG expansion responsible for this disease has the molecular characteristics that had previously only been seen for myotonic dystrophy. Further clinical and molecular characterization of both DM2 and SCA8 and the correlation of these findings to those from both DM and the polyglutamine SCAs should prove to be a fruitful means of more fully understanding the pathophysiology of both ataxia and myotonic dystrophy.

Recent Publications:

Liquori, CL, K. Ricker, ML Moseley, JF Jacobsen, W Kress, SL Naylor, JW Day, LPW Ranum. (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science: 864-867.

Moseley, ML, LJ Schut, TD Bird, MD Koob, JW Day and LPW Ranum (2000) SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Human Molecular Genetics 9:2125-2130.

Nemes, JP, KA Benzow, ML Moseley, LPW Ranum and MD Koob (2000) The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1) Human Molecular Genetics. 9:1543-1551 & Correction/Addition: Human Molecular Genetics 9:1543

Day, JW, LJ Schut, TD Bird, ML Moseley, AC Durand and LPW. Ranum (2000) Spinocerebellar ataxia type 8: clinical features in a large family. Neurology 55:649-657.

Koob, MD, ML Moseley, LJ Schut, KA Benzow, TD Bird, JW Day, and LPW Ranum (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genetics 21:379-384.

Koob, M.D., K.A. Benzow, John W. Day, T.D. Bird, M.L. Moseley, and L.P.W. Ranum (1998) Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA. Nature Genetics 18:72-75.

Ranum, LPW, PF Rasmussen, KA Benzow, MD Koob, and JW Day (1998) Genetic mapping of a second myotonic dystrophy locus (DM2). Nature Genetics 19:196-198.

Day, J.W., K. Ricker, J.J. Jacobsen, L. J. Rasmussen, K.A. Dick, W. Kress, C. Schneider, M.C. Koch, G. J. Beilman, A. R. Harrison, J.C. Dalton and L.P.W. Ranum (2003) Myotonic dystrophy type 2: molecular, diagnostic, and clinical spectrum. Neurology 60:657-664.

Liquori, C.L., Y. Ikeda, M. Weatherspoon, K. Ricker, B.G.H. Schoser, J.D. Dalton, J.W. Day, L.P.W. Ranum (2003) Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract. Am. J. Hum. Genet. 73:849-862.

Savkur, R. S., A. V. Philips, T. A. Cooper, J.C. Dalton, M.L. Moseley, L.P.W. Ranum, J.W. Day (2004) Insulin receptor splicing alteration in myotonic dystrophy type 2. American Journal of Human Genetics 74:1309-13.

Ikeda, Y., J.C. Dalton, M.L. Moseley, K.L. Gardner, T. D. Bird, T. Ashizawa, W. K.Seltzer, M. Pandolfo, A. Milunsky, N.T. Potter, M.Shoji, J.B. Vincent, J.W. Day, L.P.W. Ranum (2004) Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 ataxia families. American Journal of Human Genetics 75:3-16.

Review Articles:

Mosemiller, A.K., J. C., Dalton, J. W. Day, L. P. W. Ranum. (2003) Molecular genetics of spinocerebellar ataxia type 8. Cytogenetic and Genome Research 100:175-83.

Ranum, L.P.W. and J. W. Day (2004) Myotonic dystrophy: RNA pathogenesis comes into focus. American Journal of Human Genetics 74:793-804.

Ranum, L. P. W. and J. W. Day (2004). Pathogenic RNA repeats and their expanding role in genetic disease. Trends in Genetics 20(10): 506-512