Positions
- Professor
-
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
- Director
-
Graduate Program in Cancer & Cell Biology
Baylor College of Medicine
- Director
-
Graduate Program in Integrative Molecular and Biomedical Sciences
Baylor College of Medicine
- The Cullen Foundation Professorship in Molecular Genetics
-
Baylor College of Medicine
Houston, Texas United States
- Member
-
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
- Director
-
BCM Michigan Emory Fragile X Research Center
Baylor College of Medicine
NIH funded Center aimed at understanding mechanisms whereby premutation-length CGG repeats cause neurodegenerative and ovarian disorders.
Education
- PhD from Massachusetts Institute Of Technology
- 06/1984 - Cambridge, Massachusetts United States
- Biology
- Post-Doctoral Fellowship at National Institutes Of Health
- 01/1985 - Bethesda, MD United States
- Post-Doctoral Fellowship at Baylor College Of Medicine
- 01/1986 - Houston, TX United States
- BA from University Of Virginia
- 05/1978 - Charlottesville, Virginia United States
- Biology, Chemistry
Honors & Awards
- Editor-in-chief, American Journal of Human Genetics
- American Society of Human Genetics (01/2012 - 12/2017)
- Barbara Bowman Distinguished Texas Geneticist Award
- 2010
- Secretary, American Society of Human Genetics
- 01/2004 - 12/2009
- Cullen Foundation Chair in Molecular and Human Genetics
- 2003
- National Institute of Child Health and Human Development (NICHD) - Member, Mental Retardation Review Committee
- 2003
- Huntington Disease Society of America - Leadership Award
- 2000
- National Fragile-X Foundation - William Rosen Award
- 2000
- AAAS Fellow
- 2015
- AAAS
- President
- American Society of Human Genetics (01/2018 - 12/2018)
Professional Interests
- Human genome and disease gene analysis
- Fragile X syndrome
- Incontinentia pigmenti
- Complex genetics
Professional Statement
RESEARCH INTERESTSOne of the most exciting findings in human genetics has been the recognition that unstable trinucleotide repeats contribute to more than four dozen genetic disorders, including myotonic muscular dystrophy, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Huntington’s disease. With collaborators, Nelson described the first of these unstable DNA sequences, a polymorphic CGG trinucleotide repeat in the FMR1 gene found to be enlarged in people with fragile X syndrome, the most common form of inherited intellectual disability and autism. The mechanism by which this mutation leads to disease is through loss of function of the FMR1 gene product due to diminished expression accompanied by aberrant methylation of the gene. The FMR1 gene product is an RNA binding protein that interacts with complexes of RNA and ribosomes. It regulates the translation of hundreds of mRNAs. The Nelson group focuses on dissecting the function(s) of FMR1 and its paralogs FXR1 and FXR2. Understanding factors that lead to DNA instability of this sequence is also a key interest.
The Nelson group also studies disorders found in people with smaller expansions of the FMR1 CGG repeat, known as premutation carriers (55-200 repeats). Males with CGG repeat lengths in this range are at risk for a late-onset neurodegenerative disorder termed FXTAS. FXTAS is distinct from fragile X syndrome; individuals are cognitively unaffected until their 6th or 7th decade, but then show neuronal degeneration accompanied by neuronal nuclear inclusions that stain with ubiquitin on autopsy. The Nelson group has utilized models in flies and mice to investigate the hypothesis that a gain of function through RNA toxicity is responsible for neuronal dysfunction and death. Fly models allowed identification and characterization of modifiers, and mouse models showed definitively that the CGG repeat was both necessary and sufficient to affect mammalian neurons. The group is also studying fragile X-associated primary ovarian insufficiency, (FXPOI) a disorder resulting in early menopause found in some female carriers of the premutation. Using mouse models, the group has improved understanding of the mechanism of ovarian insufficiency. Identifying genetic modifiers in both FXTAS and FXPOI is a goal for potential therapies. The group has demonstrated roles for several RNA-binding proteins including TDP-43 and alterations in 5-hydroxymethylcytosine, suggesting widespread dysregulation of gene expression.
The Nelson group was involved in numerous aspects of the Human Genome Project, with key input into the mapping and sequencing of the human X chromosome, and participation in several other sequencing projects, from fruit fly to Rhesus monkey. Dr. Nelson's group identified gene mutations in other disorders such as Incontinentia Pigmenti and FRAXE intellectual disability. He also has interest in the genetic contribution to common disorders such as cancer, and has investigated the potential role of common variants in genes involved in DNA repair in human disease.
Websites
Selected Publications
- Kang JY, Wen Z, Pan D, Zhang Y, Li Q, (…), Nelson DL, Guo X, Zhou Y, Gou LT, Huang Y, Liu MF "LLPS of FXR1 drives spermiogenesis by activating translation of stored mRNAs." Science. 2022;377:eabj6647. Pubmed PMID: 35951695
- Yildirim Z, Baboo S, Hamid SM, Dogan AE, Tufanli O, (…), Nelson DL, Yates JR 3rd, Walter P, Erbay E "Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression." EMBO Mol Med.. 2022;14:e15344. Pubmed PMID: 35191199
- Kong HE, Lim J, Linsalata A, Kang Y, Malik I, (…), Nelson DL, Epstein MP, Cutler DJ, Todd PK, Sherman SL, Warren ST, Jin "Identification of PSMB5 as a genetic modifier of fragile X-associated tremor/ataxia syndrome." Proc Natl Acad Sci U S A. 2022;119:e2118124119. Pubmed PMID: 35617426
- Shelly KE, Candelaria NR, Li Z, Allen EG, Jin P, Nelson DL "Ectopic expression of CGG-repeats alters ovarian response to gonadotropins and leads to infertility in a murine FMR1 premutation model.." Hum Mol Genet.. 2021;30:923-938.
- Kong HE, Lim J, Zhang F, Huang L, Gu Y, Nelson DL, Allen EG, Jin P "Metabolic pathways modulate the neuronal toxicity associated with fragile X-associated tremor/ataxia syndrome.." Hum Mol Genet. 2019;28:980-991.
- Estañ MC, Fernández-Núñez E, Zaki MS, Esteban MI, Donkervoort S, Hawkins C, (…), Nelson DL, Otaify GA, Temtamy S, Aglan M, Issa M, Bönnemann CG, Lapunzina P, Yoon G, Ruiz-Perez VL "Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy.." Nat Commun.. 2019;10:797.
- Higashimori H, Schin CS, Chiang MS, Morel L, Shoneye TA, Nelson DL, Yang Y "Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo.." J Neurosci. 2016;36:7079-94.
- Lumaban JG, Nelson DL "The Fragile X proteins Fmrp and Fxr2p cooperate to regulate glucose metabolism in mice." Hum Mol Genet. 2015 Apr 15;24:2175-84. Pubmed PMID: 25552647
- Cook D, Nuro E, Jones EV, Altimimi HF, Farmer WT, Gandin V, Hanna E, Zong R, Barbon A, Nelson DL, Topisirovic I, Rochford J, Stellwagen D, Béïque JC, Murai KK "FXR1P limits long-term memory, long-lasting synaptic potentiation, and de novo GluA2 translation." Cell Rep. 2014 Nov;9:1402-16. Pubmed PMID: 25456134
- Galloway JN, Shaw C, Yu P, Parghi D, Poidevin M, Jin P, Nelson DL "CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome." Hum Mol Genet. 2014 Nov 15;23:5906-15. Pubmed PMID: 24986919
- Yao B, Lin L, Street RC, Zalewski ZA, Galloway JN, Wu H, Nelson DL, Jin P "Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of fragile X-associated tremor/ataxia syndrome." Hum Mol Genet. 2014 Feb;23:1095-107. Pubmed PMID: 24108107
- Nelson DL, Orr HT, Warren ST "The unstable repeats-three evolving faces of neurological disease.." Neuron. 2013 Mar 6;77(5):825-43. Pubmed PMID: 23473314
- Lee J, Moulik M, Fang Z, Saha P, Zou F, Xu Y, Nelson DL, Ma K, Moore DD, Yechoor VK "Bmal1 and ß-Cell Clock Are Required for Adaptation to Circadian Disruption, and Their Loss of Function Leads to Oxidative Stress-Induced ß-Cell Failure in Mice.." Mol. Cell. Biol.. 2013 Jun;33(11):2327-38. Pubmed PMID: 23547261
- Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, Jin P "Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration.." Proc. Natl. Acad. Sci. U.S.A.. 2013 May 7;110(19):7778-83. Pubmed PMID: 23553836
- Vislay RL, Martin BS, Olmos-Serrano JL, Kratovac S, Nelson DL, Corbin JG, Huntsman MM "Homeostatic responses fail to correct defective amygdala inhibitory circuit maturation in fragile x syndrome.." J. Neurosci.. 2013 Apr 24;33(17):7548-58. Pubmed PMID: 23616559
- Yrigollen CM, Durbin-Johnson B, Gane L, Nelson DL, Hagerman R, Hagerman PJ, Tassone F "AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome.." Genet. Med.. 2012 Aug;14(8):729-36. Pubmed PMID: 22498846
- Qurashi A, Liu H, Ray L, Nelson DL, Duan R, Jin P "Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila.." Hum. Mol. Genet.. 2012 May 1;21(9):2068-75. Pubmed PMID: 22298836
- Tan H, Qurashi A, Poidevin M, Nelson DL, Li H, Jin P "Retrotransposon activation contributes to fragile X premutation rCGG-mediated neurodegeneration.." Hum. Mol. Genet.. 2012 Jan 1;21(1):57-65. Pubmed PMID: 21940752
- Whitman SA, Cover C, Yu L, Nelson DL, Zarnescu DC, Gregorio CC "Desmoplakin and talin2 are novel mRNA targets of fragile x-related protein-1 in cardiac muscle.." Circ. Res.. 2011 Jul 22;109(3):262-71. Pubmed PMID: 21659647
- Guo W, Allan AM, Zong R, Zhang L, Johnson EB, Schaller EG, Murthy AC, Goggin SL, Eisch AJ, Oostra BA, Nelson DL, Jin P, Zhao X "Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning.." Nat. Med.. 2011 May;17(5):559-65. Pubmed PMID: 21516088
- Hashem V, Galloway JN, Mori M, Willemsen R, Oostra BA, Paylor R, Nelson DL "Ectopic expression of CGG containing mRNA is neurotoxic in mammals.." Hum. Mol. Genet.. 2009 Jul 1;18(13):2443-51. Pubmed PMID: 19377084
- Peier AM, McIlwain KL, Kenneson A, Warren ST, Paylor R, Nelson DL "(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features.." Hum. Mol. Genet.. 2000 May 1;9(8):1145-59. Pubmed PMID: 10767339
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