Overview

Our lab uses mouse models to identify the molecular pathways underlying degenerative motor neuron diseases in humans, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease). We cloned the gene for neuromuscular degeneration to create a mouse model for a lethal infantile form of SMA known as spinal muscular atrophy with respiratory distress. Studying the mouse model led to the identification of a modifier gene that decreases disease severity in the mice. In addition, we are working with a transgenic mouse strain (SOD1) to study genetic background effects on progression of an ALS-like disease in the mouse model.

We are also studying mouse models for degenerative muscle diseases similar to muscular dystrophy in humans. We cloned a genetic defect and have localized the mutation to the muscle-specific titin gene, the largest known coding gene in the mammalian genome. The mouse strain is a novel model of progressive muscular dystrophy and may also be a model for human tibial muscular dystrophy and limb-girdle muscular dystrophy type 2J. We also identified the mutation for a new form of rostrocaudal muscular dystrophy that affects skeletal muscle tissues in a unusual front-to-back progression.

Scientific report

Mouse Models of Neuromuscular Disease

The long-term goal of our research program is to identify molecular pathways necessary for the normal function and survival of motor neurons and their skeletal muscle targets. Muscular dystrophies and motor neuron diseases collectively have a high impact on health, affecting tens of thousands of people in the United States alone. The diseases are characterized by weakness and progressive wasting of muscles, eventually leading to paralysis and death. We have chosen to focus on the resources available at The Jackson Laboratory in the form of spontaneous and induced models of neuromuscular disease as our starting point for gene discovery and functional analysis. This phenotype-driven approach ensures that the mutant genes we identify are critical for the normal development and/or maintenance of motor neurons and skeletal muscles.

A mouse model of spinal muscular atrophy with respiratory distress

Neuromuscular degeneration, nmd, is a spontaneous autosomal recessive mouse mutant characterized by severe hindlimb muscle atrophy due to progressive degeneration of spinal motor neurons. We identified the mutant nmd gene as immunoglobulin mu binding protein 2 (Ighmbp2), a member of the DNA helicase/ATPase family of proteins. Mutations in the human IGHMBP2 gene have been shown to cause a lethal infantile form of spinal muscular atrophy with respiratory distress (SMARD1). As the nmd mice develop the same motor neuron disease as children with SMARD1, we are hopeful that what we learn from these mice will be directly relevant to the human disease. Toward this goal, we are employing powerful genetic approaches to identify the critical cell types that require Ighmbp2 gene activity in transgenic mice. We have demonstrated that tissue-specific expression of IGHMBP2 in neurons completely rescues the motor neuron degeneration, but it also uncovered a previously unrecognized requirement for this gene product in cardiac muscle. The transgenic nmd mice show no signs of paralysis but do develop a progressive dilated cardiomyopathy (DCM). Similarly, skeletal and cardiac-specific Ighmbp2 transgenic lines rescue the cardiomyopathy independent of the motor neurons and increased the lifespan of nmd mice up to 8-fold.

Identifying a genetic modifier of nmd

The effects of modifier genes in human cases of amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA) have been implied when intrafamilial heterogeneity in age of onset or severity of symptoms are encountered. However, the possible multifactorial nature of these modifiers and genetic heterogeneity among families limit the extent to which genetic linkage can be performed in human populations. During the course of fine-mapping the nmd gene, we identified a modifier gene on Chromosome 13 that greatly decreases the severity of disease. We have generated a B6 congenic mouse strain that contains the CAST-derived Mnm modifier locus to allow high-resolution genetic mapping and positional cloning. We have reduced the size of the genetic region that is known to contain the Mnm modifier gene to a 160 kb interval, and the disease can be completely suppressed using a CAST BAC clone as a transgene. Our ability to manipulate the severity of disease with at least one modifier gene suggests that a molecular pathway exists with the potential for genetic or clinical intervention.

Mapping genetic modifiers of amyotrophic lateral sclerosis

Along with colleague Kevin Seburn at The Jackson Laboratory, we are testing the hypothesis that genetic background effects can modify the onset or progression of ALS symptoms in the G93A mutant SOD1 transgenic mouse model. Using a strain survey with several wild-derived and common inbred strains of mice, we have identified two inbred strains (ALR/LtJ and NOD/LtJ) that significantly accelerate the onset of disease and three that significantly delay disease onset (C57BL/6J, DBA/2J and BALB/cByJ). Reciprocal backcrosses between C57BL/6J and ALR/LtJ have permitted the mapping of quantitative trait loci that underlie the suppression or enhancement of the motor neuron disease in G93A SOD1 (Tg(SOD1-G93A)1Gur) transgenic mice. Identification of these polymorphic loci is likely to provide insights into the mechanism of disease and possible genetic targets for intervention.

Defining the functional role of titin in mdm muscular dystrophy

Muscular dystrophy with myositis (mdm) is an autosomal recessive mutation located on Chromosome 2 that leads to progressive degeneration of skeletal muscles. We identified the mdm mutation as a deletion and truncated LINE insertion in the muscle-specific titin (Ttn) gene and have explored its potential interaction with the muscle-specific protease calpain 3. The discovery of this model at The Jackson Laboratory proved to be the first muscular dystrophy mutation identified in the Ttn gene, which encodes the largest known protein in the mammalian genome (>100 kb mRNA, ~370 exons, 3.7 megadalton protein). The mdm mouse serves as a model for human limb-girdle muscular dystrophy 2J and tibial muscular dystrophy. We are currently generating an allelic series of muscular dystrophy mutations at the Ttn locus using a sensitized ENU mutagenesis screen to identify critical functional or ligand-binding domains as well as defining the role of TTN in muscle cell development and degenerative muscular dystrophies.

A novel disease mechanism identified in rostrocaudal muscular dystrophy (rmd)

Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation that causes a rapidly progressive muscular dystrophy and a neonatal forelimb bone deformity. We identified the rmd mutation in the choline kinase beta (Chkb) gene, resulting in a complete loss of CHKB protein and enzymatic activity. Choline kinase catalyzes the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine (PC). While mutant rmd mice show a dramatic decrease of CHK activity in all tissues, the dystrophy is only evident in skeletal muscle tissues in an unusual rostral-to-caudal gradient. Enlarged mitochondria are evident in rmd muscles, suggesting that dysregulation of energy metabolism may underlie the muscle disease. The rmd mutant mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy.

Generating a mouse model of Familial Paraganglioma

Paragangliomas are tumors of neural crest origin that develop from extra-adrenal sympathetic paraganglia of the abdomen, thorax or head and neck regions. These neuroendocrine tumors often secrete adrenaline or noradrenaline, which can lead to severely elevated blood pressure. Most sporadic paragangliomas are benign and surgical removal has proven to be an effective treatment. However, for familial cases, tumors recur frequently and can become metastatic, at which point clinical treatments such as radiotherapy and chemotherapy are generally ineffective. Loss of function mutations in either succinate dehydrogenase subunit B (SDHB), SDHC or SDHD have been shown to cause familial paraganglioma and each requires a second somatic mutation in the wild-type allele to initiate tumorigenesis. Currently, no model systems exist for these cancers to provide the critical tools necessary for discovery and testing of effective therapeutic strategies. We have generated mice carrying loss of function alleles in the Sdhb and Sdhc genes from an available mouse embryonic stem cell gene trap library to create genetic models of this unique human cancer. The Sdhb and Sdhc heterozygous mutant mice will be screened for development of spontaneous tumors and the phenotypic changes associated with paragangliomas such as catecholamine production and severe hypertension. Irradiation of the heterozygous +/- carriers to induce loss of heterozygosity (LOH) will be used to potentially increase the penetrance and reduce the age of onset of paragangliomas. The creation of a reproducible model system could have important implications for the clinical management of patients and spur new drug development. 

Lab staff

Research Scientist: Kevin L. Seburn, Ph.D.
Postdoctoral Fellows:  Roger B. Sher, Ph.D., Prabakaran Soundararajan, Ph.D.
Research Assistant: David G. Schroeder, B.S.
Research Administrative Assistant: Maxine Friend

Publication listings

Chamberlain JS, Farwell NJ, Ranier JE, Cox GA, Caskey CT.  1991. PCR analysis of dystrophin gene mutation and expression.  J.Cell Biochem. 46:255-259.

Cox GA, Phelps SF, Chapman VM, Chamberlain JS.  1993. New mdx mutation disrupts expression of muscle and nonmuscle isoforms of dystrophin.  Nature Genetics 4:87-93.

Cox GA, Cole NM, Matsumura K, Phelps SF, Hauschka SD, Campbell KP, Faulkner JA, Chamberlain JS.  1993.  Overexpression of dystrophin in transgenic mdx mice eliminates dystophic symptoms without toxicity.  Nature 364:725-729.

Denetclaw WF, Jr., Hopf FW, Cox GA, Chamberlain JS, Steinhardt RA.  1994.  Myotubes from transgenic mdx mice expressing full-lenght dystrophin show normal calcium regulation.  Mol. Biol. Cell 5:1159-1167.

Cox GA, Sunada Y, Campbell KP, Chamberlain JS.  1994.  Dp71 can restore the dystrophin-associated glycoprotein complex in muscle but fails to prevent dystrophy.  Nature Genetics 8:333-339.

Rafael JA, Cox GA, Corrado K, Jung D, Campbell KP, Chamberlain JS.  1996.  Forced expression of dystrophin deletion constructs reveals structure-function correlations.  J. Cell Biol. 134:93-102.

Cox GA, Lutz CM, Yang C-L, Biemesderfer D, Bronson RT, Fu, A, Aronson PS, Noebels JL, Frankel WN.  1997.  Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice.  Cell 91:139-148.

Cox GA, Mahaffey CL, Frankel WN.  1998.  Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele.  Neuron 21:1327-1337.

Lumerg CN, Phelps SF, Rafael JA, Cox GA, Hutchinson TL, Begy CR, Adkins E, Wiltshire R, Chamberlain JS.  1999.  Characterization of dystrophin and utrophin diversity in the mouse.  Hum. Mol. Genet. 8:593-599.

Cox GA, Mahaffey CL, Nystuen A, Letts VA, Frankel WN.  2000.  The mouse fidgetin gene defines a new role for AAA family proteins in mammalian development.  Nat. Genet. 26:198-202.

Sundberg JP, Boggess D, Shultz LD, Fijneman RJ, Demant P, HogenEsch H, Cox GA.  2000.  The chronic  proliferative dermatitis mouse mutation (cpdm): mapping of the mutant gene locus.  J Exp Anim Sci 41:101-108.

Garvey SM, Rajan C, Lerner AP, Frankel WN, Cox GA.  2002.  The Muscular Dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin.  Genomics 79:146-149.

Sundberg JP, Boggess D, Silva KA, McElwee KJ, King LE, Li R, Churchill G, Cox GA.  2003.  Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice.  J. Invest. Dermatol.  120:771-775.

Serreze DV, Pierce MA, Post CM, Chapman HD, Savage H, Bronson RT, Rothman PB, Cox GA.  2003. Paralytic autoimmune myositis develops in addition to type 1 diabetes in NOD mice made Th1 cytokin deficient by expression of an IFNg receptor β chain transgene. J Immunology 170:2742-2749.

Maddatu TP, Garvey SM, Shroeder DG, Hampton TG, Cox GA.  2004.  Transgenic rescue of neurogenic atrophy in the nmd mouse reveals a role for Ighmbp2 in dilated cardiomyopathy.  Hum. Mol. Genet. 13:1105-1115.

Sunberg JP, Silva KA, Li R, Cox GA, King LE.  2004.  Adult onset alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model.  J. Invest. Dermatol. 123:294-297.

Ho M, Post CM, Donahue LR, Lidov HGW, Bronson RT, Goolsby H, Watkins SC, Cox GA, Brown RH Jr.  2004.  Disruption of muscle membrane and phenotype divergence in two mouse models of dysferlin-deficiency.  Hum. Mol. Genet. 13:1999-2010.

Wooley CM, Sher RB, Kale A, Frankel WN, Cox GA, Seburn KL.  2005. Gait analysis detects early changes in transgenic SOD1(G93A) mice. Muscle Nerve. 32:43-50.

Lee Y, Kameya S, Cox GA, Hsu J, Hicks W, Maddatu TP, Smith RS, Naggert JK, Peachey NS, Nishina PM. 2005. Ocular abnormalities in Large (myd) and Large (vls) mice, spontaneous models in muscle, eye, and brain diseases. Mol Cell Neurosci 30:160-72.

Huebsch KA, Kudryashova E, Wooley CM, Sher RB, Seburn KL, Spencer MJ, Cox GA.  2005.  Mdm Muscular Dystrophy: Interactions with Calpain 3 and a Novel Functional Role for Titin's N2A Domain. Hum Mol Genet 14:2801-11.

Maddatu TP, Garvey SM, Schroeder DG, Zhang W, Kim SY, Nicholson AI, Davis CJ, Cox GA.  2005.  Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival  Hum Mol Genet. 14:3179-89.

Hadano S, Benn SC, Kakuta S, Otomo A, Sudo K, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Shefner JM, Cox GA, Iwakura Y, Brown RH Jr, Ikeda JE.  2006.  Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking  Hum Mol Genet. Jan 15;15(2):233-50.

Tarchini B, Huynh TH, Cox GA, Duboule D.  2005.  HoxD cluster scanning deletions identify multiple defects leading to paralysis in the mouse mutant Ironside.  Genes Dev. Dec 1;19(23):2862-76.

Sher RB, Aoyama C, Huebsch KA, Ji S, Kerner J, Yang Y, Frankel WN, Hoppel CL, Wood PA, Vance DE, Cox GA.  2006.  A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis.  J Biol Chem.  Feb 24;281(8):4938-48.

Mikaelian I, Hovick M, Silva KA, Burzenski LM, Shultz LD, Ackert-Bicknell CL, Cox GA, Sundberg JP.  2006  Expression of terminal differentiation proteins defines stages of mouse mammary gland development.  Vet Pathol. Jan;43(1):36-49.

Runkel F, Bussow H, Seburn KL, Cox GA, Ward DM, Kaplan J, Franz T.  2006.  Grey, a novel mutation in the murine Lyst gene, causes the beige phenotype by skipping of exon 25.  Mamm Genome 17:203-10.

Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW.  2006.  An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model.  Neuron 51:715-26.
 
Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP.  2007.  Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis.  Genes Immun. 8:416-21.

Yang Y, Mahaffey CL, Berube N, Maddatu TP, Cox GA, Frankel WN.  2007.  Complex seizure disorder caused by Brunol4 deficiency in mice.  PLoS Genet. 3:e124.

Maltecca F, Aghaie A, Schroeder DG, Cassina L, Taylor BA, Phillips SJ, Malaguti M, Previtali S, Guénet JL, Quattrini A, Cox GA, Casari G. 2008. The mitochondrial protease AFG3L2 is essential for axonal development. J Neurosci 28:2827-36.

Ackerman SL, Cox GA. 2008. From ER to Eph receptors: new roles for VAP fragments. Cell 13:949-51.

Lopez MA, Pardo PS, Cox GA, Boriek AM. 2008. Early mechanical dysfunction of the diaphragm in the muscular dystrophy with myositis (Ttnmdm) model. Am J Physiol Cell Physiol 295:C1092-102. PMC2584999

Walters BJ, Campbell SL, Chen PC, Taylor AP, Schroeder DG, Dobrunz LE, Artavanis-Tsakonas K, Ploegh HL, Wilson JA, Cox GA, Wilson SM. 2008. Differential effects of Usp14 and Uch-L1 on the ubiquitin proteasome system and synaptic activity. Mol Cell Neurosci 39:539-48. PMC2734958

Cohen TJ, Barrientos T, Hartman ZC, Garvey SM, Cox GA, Yao TP. 2009. The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity. FASEB J 23:99-106. PMC2626618

Wooley CM, Xing S, Burgess RW, Cox GA, Seburn KL. 2009. Age, experience and genetic background influence treadmill walking in mice. Physiol Behav 96:350-61. PMC2759980

Wu G, Sher RB, Cox GA, Vance DE. 2009. Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice. Biochim Biophys Acta 1791:347-56.

de Planell-Saguer M, Schroeder DG, Rodicio MC, Cox GA, Mourelatos Z. 2009. Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. Hum Mol Genet 18:2115-26. PMC2685751

Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G.  2009.  Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration.  J Neurosci. 29:9244-54.

Chase TH, Cox GA, Burzenski L, Foreman O, Shultz LD.  2009.  Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B. AM J Pathol 175:2299-308. PMC2789639

Lee BJ, Cox GA, Maddatu TP, Judex S, Rubin CT.  2009.  Devastation of bone tissue in the appendicular skeleton parallels the progression of neuromuscular disease.  J Musculoskelet Neuronal Interact. 9:215-24.

Burgess RW, Cox GA, Seburn KL. 2010. Neuromuscular disease models and analysis. Methods Mol Biol. 602:347-393.

Wu G, Sher RB, Cox GA, Vance DE. 2009. Differential expression of choline kinase isoforms in skeletal muscle explains the phenotypic variability in the rostrocaudal muscular dystrophy mouse. Biochim Biophys Acta. 1801:446-54.

Mohamed JS, Lopez MA, Cox GA, Boriek AM. 2010. Anisotropic regulation of Ankrd2 gene expression in skeletal muscle by mechanical stretch. FASEB J 24:3330-40. PMC2923360

Mitsuhashi S, Ohkuma A, Talim B, Karahashi M, Koumura T, Aoyama C, Kurihara M, Quinlivan R, Sewry C, Mitsuhashi H, Goto K, Koksal B, Kale G, Ikeda K, Taguchi R, Noguchi S, Hayashi YK, Nonaka I, Sher RB, Sugimoto H, Nakagawa Y, Cox GA, Topaloglu H, Nishino I.  2011.  A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis.  Am J Hum Genet. 88:845-851. PMC3113344

Mitsuhashi S, Hatakeyama H, Karahashi M, Koumura T, Nonaka I, Hayashi YK, Noguchi S, Sher RB, Nakagawa Y, Manfredi G, Goto Y, Cox GA, Nishino I. 2011. Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy. Hum Mol Genet. 20:3841-3851. PMC3168292

Sher RB, Cox GA, Mills KD, Sundberg JP. 2011. Rhabdomyosarcomas in aging A/J mice. PLoS One. 6:e23498. PMC3154500

Stroklin M, Seburn KL, Cox GA, Martens KA, Reiser G. 2012. Severe disturbance in the Ca2+ signaling in astrocytes from mouse models of human infantile neuroaxonal dystrophy with mutated PIa2g6. Hum Mol Genet. 21:2807-2814. PMC3363330

Su YQ, Sugiura K, Sun F, Pendola JK, Cox GA, Handel MA, Schimenti JC, Eppig JJ. 2012. MARF1 regulates essential oogenic processes in mice. Science. 335:1496-1499.

Choi MC, Cohen TJ, Barrientos T, Wang B, Li M, Simmons BJ, Yang JS, Cox GA, Zhao Y, Yao TP. 2012. A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Mol Cell. 47:122-132. PMC3398192

Hosur V, Kavirayani R, Riefler J, Carney LM, Lyons B, Gott G, Cox GA, Shultz LD. 2012. Dystrophin and dysferlin double mutant mice: a novel model for rhabdomyosarcoma. Cancer Genet. 205:232-241. PMC3372852

Hoffman EP, Gordish-Dressman H, McLane VD, Devaney JM, Thompson PD, Visich P, Gordon PM, Pescatello LS, Zoeller RF, Moyna NM, Angelopoulos TJ, Pegoraro E, Cox GA, Clarkson PM. 2012. Alterations in osteopontin modify muscle size in females in both humans and mice. Med Sci Sports Exerc. (Epub ahead of print). 

Books, Book Chapters and Reviews Ex

Chamberlain JS, Phelps SF, Cox GA, Maichele AJ, Greenwood AD.  1993.  PCR analysis of muscular dystrophoy in mdx mice.  In: Molecular and Cell Biology of Muscular Dystrophy, Partridge T (ed), Chapman & Hall. 167-189.

Chamberlain JS, Corrado K, Rafael JA, Cox GA, Hauser M, Lumeng C.  1997.  Interactions between dystrophin and the sarcolemma membrane.  In: Cytoskeletal Regulation of Membrane Function (ed. Froehner SC and Bennett V, The Rockefeller University Press, New York): 19-29

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