Dr. Laura P.W. Ranum
Laura P.W. Ranum, Ph.D.
Director of Center for NeuroGenetics
Professor of UF MGM
Phone: (352) 294-5209
Fax: (352) 273-8284
University of Florida
Dept. of Molecular Genetics & Microbiology
2033 Mowry Rd.
Gainesville, FL. 32610
Areas of Research Strength
Neuroscience, Human Genetics, Muscular Dystrophy, Ataxia, Amyotrophic Lateral Sclerosis
Research Techniques Used
Human genetics, genetic mapping, positional cloning, transgenic models
Many neurodegenerative diseases begin later in life after the nervous system is fully developed. A major step towards a better understanding of neurodegenerative diseases was made with the discovery that microsatellite repeat expansions are responsible for a large group (>30) of these diseases. In these disorders, extra copies of short DNA repeats (e.g. CTG•CAG or CCTG•CAGG) cause disease. In general, these mutations are thought to cause disease by protein loss-of-function, protein gain-of-function or by RNA gain of function mechanisms. My group uses human genetics to define the molecular causes of neurological disorders and mouse models to understand how these mutations cause neurons in the brain to die.
RNA gain-of-function in SCA8 and DM: In 1999 we discovered that a novel form of ataxia, spinocerebellar ataxia type 8 (SCA8), is caused by a CTG•CAG expansion mutation (Nature Genetics 21:379-384). In 2001 we showed that a second form of myotonic dystrophy (DM2) is caused by an intronic CCTG•CAGG tetranucleotide expansion (Science 293:864-867). These discoveries and additional work by others have established that CUG/CCUG expansion RNAs dysregulate alternative splicing pathways. To understand the impact of these expansion mutations on the central nervous system (CNS) we developed SCA8 and DM mouse models (Nature Genetics 38:758-769, 2006). Our SCA8 mice showed, for the first time, that CUG expansion transcripts cause RNA gain-of-function effects in the brain and that relatively short expansions (~100 repeats) are sufficient in length to effect these changes (Plos Genetics 5:e1000600, 2009). We are currently characterizing our DM and SCA8 mice using a combination of molecular and in vivo optical-imaging strategies to determine if specific alternative splicing changes caused by CUG and CCUG expansion transcripts lead to neuronal phenotypes.
Bidirectional expression of expansion mutations: A second discovery my group made in SCA8, was that the CTG•CAG expansion mutation is bidirectionally transcribed and in addition to CUGEXP transcripts the expansion mutation also produces CAGEXP transcripts that expresses a polyglutamine expansion protein. Both polyGln aggregates and CUG-containing RNA foci accumulate in cerebellar Purkinje cells, which are a primary site of neurodegeneration in the disease. The expression of noncoding CUGEXP transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions expressed from ataxin 8 (ATXN8) CAG transcripts suggested SCA8 pathogenesis involves toxic gain of function mechanisms at both the protein and RNA levels. It is now clear that much of the genome and a growing number of expansion loci including the DM1, FMR1, HD, HDL2, SCA7 and C9orf72 ALS/FTD expansion mutations are bidirectionally transcribed raising the possibility that both sense and antisense transcripts contribute to a broad group of neurological diseases.
Repeat Associated Non-AUG Translation (RAN Translation): In 2011 we reported that the canonical rules of translation do not apply for CTG•CAG repeat expansions and that CAG and CUG expansion transcripts can express homopolymeric expansion proteins in all three frames without an AUG start codon. We showed that this repeat-associated non-ATG (RAN) translation is hairpin dependent, occurs without frameshifting or RNA editing and is observed in cell culture and SCA8 patient tissues. Additionally, we showed a novel RAN proteins accumulate in both SCA8 and DM1 patient tissues. As expected our 2011 discovery of RAN translation was highly controversial because it went against the established dogma. For more than two decades the position of the expansion mutation, within or outside an ATG-initiated open reading frame (ORF), provided the framework for research into the molecular consequences of these mutations. The discoveries of bidirectional transcription and RAN translation highlight the need to test therapeutic strategies that target both sense and antisense transcripts as well as RAN proteins. In 2013, additional studies by our group and others in C9ORF72 ALS/FTD have demonstrated that both sense and antisense RNA foci and RAN proteins expressed from all six reading frames accumulate in patient autopsy tissue. RAN proteins have also been reported in the CGG expansion disorder fragile-X tremor ataxia syndrome (FXTAS). We are now addressing a number of provocative questions that this discovery raises including: 1) How does this novel translational initiation mechanism work? 2) Is RAN-translation a key, previously unrecognized, pathogenic mechanism in neurologic disease? 3) Are other repetitive sequences in the genome translated into proteins and if so, what is their function?
Spectrin mutations in SCA5. My lab is also involved in the discovery and characterization of other types of novel gene mutations. In 2006 we showed spinocerebellar ataxia type 5 (SCA5), is caused by mutations in the spectrin beta non-erythrocytic 2 (SPTBN2) gene (Nature Genetics 38:184-90, 2006) which encodes the β-III spectrin protein. We recently developed novel mouse and fly models of SCA5 to better understand how SBTBN2 mutations affect protein function and to model the human disease. Additional studies focus on understanding how mutations in SPTBN2 alter cellular function and cause disease.
Novel Human Gene Discovery. Additionally, my laboratory continues to search for novel human disease genes. We are using high-throughput sequencing strategies to look for single-gene mutations that cause novel forms of ataxia, amyotrophic lateral sclerosis (ALS) and neuropsychiatric diseases.
Armbrust, K.R. X. Wang, T. Hathorn, S.W. Cramer, G. Chen, T. Zu, T. Obu, A.N. Zink, G. Öz T.J. Ebner and L.P.W. Ranum. (2014) mGluR1α mislocalization and LTP deficits in a mouse model of spinocerebellar ataxia type 5. J. Neuroscience 34(30): 9891-9904.
Zu T, Y. Liu, M. Bañez-Coronel, T. Reid, O. Pletnikova, J. Lewis, T.M. Miller, M.B. Harms, A.E. Falchook, S.H. Subramony, L.W. Ostrow, J.D. Rothstein, J.C. Troncoso, L.P.W. Ranum (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 110:E4968-77. 1315438110.
Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, Nan Z, Forster C, Low WC, Schoser B, Somia NV, Clark HB, Schmechel S, Bitterman PB, Gourdon G, Swanson MS, Moseley M, Ranum LPW. (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl. Acad. Sci. USA 108(1):260-265.
Lorenzo DN, Li MG, Mische SE, Armbrust KR, Ranum LPW, Hays TS. (2010) Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila. J. Cell Biology 189(1):143-158.
Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, Swanson MS, Ranum LPW. (2009) RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 5(8):e1000600.
Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, Chen G, Weatherspoon MR, Clark HB, Ebner TJ, Day JW, Ranum LPW. (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat. Genet. 38(7): 758-769.
Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, Stevanin G, Dürr A, Zühlke C, Bürk K, Clark HB, Brice A, Rothstein JD, Schut LJ, Day JW, Ranum LPW. (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nature Genetics 38(2): 184-190.
Liquori, CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LPW (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 293: 864-867.
Koob, MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LPW (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) Nature Genetics 21:379-384.
Cleary J.D., L.P.W. Ranum. (2014) Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev. 26:6-15.
Ikeda Y, Daughters RS, Ranum LPW. (2008) Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum 7(2): 150-158.
Ranum LPW, Cooper TA. (2006) RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29: 259-277.
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