Abstract

The goal of this Multicenter ROt is to identify genetic risk factors that predispose individuals to amyotrophic lateral sclerosis (ALS). This RO1 is a continuation of collaborative efforts that have been ongoing since 1993, when this group identified the first ALS gene (the SOD 1 gene). Our Amyotrophic Lateral Sclerosis Genetics Collaborative Group (ALSGCG) has greatly extended the genetic knowledge of ALS by identifying loci on chromosomes 2, 9, 15, 16, 18, 20 and X using large autosomal dominant families; we have generated preliminary data for additional loci on chromosomes 1, 2, 7, 8, 17, 18, and 19 in smaller multiplex families. The ALSGCG represents the collaborative efforts of groups at Northwestern University Feinberg School of Medicine (NUFSM), Massachusetts General Hospital (MGH), Duke University Medical Center (DUMC), and Vanderbilt University Medical School (VUMS). We have collected the largest set of multiplex and singleton resources in the world and now have sufficient family material to begin gene discovery within these regions and test candidate genes as they become available. This RO1 is carried out at four sites. Site 1 (NUFSM) will use the locational candidate approach to identify the genes arising in the smaller multiplex families. This will include refining the linkage peaks using linkage analysis and testing candidate genes using allelic association studies. Site 2 (MGH) will use the locational candidate approach to identify the genes arising in the large autosomal dominant families using approaches similar to Site 1. It will also test the potential role of other motor neuron disease genes in ALS using an allelic association approach. The sites are supported by an Administrative Assistant from Northwestern, and a Genetic Epidemiology and Bioinformatics supported programs at DUMC and VUMS. Analysis of all data from the projects, including clinical, risk factor, pedigree, and genotypic data for NUFSM (Site 1) and MGH (Site 2) is carried out at DUMSC and VUMS analyses sites. Those also provide all linkage and allelic association analyses for Sites 1 and 2.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050641-04
Application #
7232013
Study Section
Special Emphasis Panel (ZNS1-SRB-E (05))
Program Officer
Refolo, Lorenzo
Project Start
2004-05-15
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$719,484
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Kim, Myung Jong; Deng, Han-Xiang; Wong, Yvette C et al. (2017) The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking. Hum Mol Genet 26:729-741
Ajroud-Driss, Senda; Fecto, Faisal; Ajroud, Kaouther et al. (2015) Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy. Neurogenetics 16:1-9
Volpe, Nicholas J; Simonett, Joseph; Fawzi, Amani A et al. (2015) Ophthalmic Manifestations of Amyotrophic Lateral Sclerosis (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc 113:T12
Fawzi, Amani A; Simonett, Joseph M; Purta, Patryk et al. (2014) Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation. Amyotroph Lateral Scler Frontotemporal Degener 15:569-80
Gorrie, George H; Fecto, Faisal; Radzicki, Daniel et al. (2014) Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proc Natl Acad Sci U S A 111:14524-9
Ahmeti, Kreshnik B; Ajroud-Driss, Senda; Al-Chalabi, Ammar et al. (2013) Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. Neurobiol Aging 34:357.e7-19
Quinlan, K A; Schuster, J E; Fu, R et al. (2011) Altered postnatal maturation of electrical properties in spinal motoneurons in a mouse model of amyotrophic lateral sclerosis. J Physiol 589:2245-60
Fecto, Faisal; Shi, Yong; Huda, Rafiq et al. (2011) Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. J Biol Chem 286:17281-91
Deng, Han-Xiang; Chen, Wenjie; Hong, Seong-Tshool et al. (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211-5
Klein, C J; Shi, Y; Fecto, F et al. (2011) TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology 76:887-94

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