We plan to fine-map and identify a gene on Chromosome 21 that causes familial amyotrophic lateral sclerosis (FALS). Defining the precise location of this gene will allow us to isolate it and study its function. Our mapping strategy is fourfold: (1) We will generate highly polymorphic DNA markers (such as (CA)n repeat(s) around the putative locus of the FALS gene on Chromosome 21 from previously mapped cosmid and yeast artificial chromosomes markers. These markers will be tested by linkage analysis in our FALS families in order to obtain the optimum genetic information from them. Crossovers between the disease (FALS) locus and the markers will help define the precise location of the FALS gene. (2) Once flanking markers are defined we will construct a band- specific genomic library by microdissection of chromosome 21. (3) We will test candidate FALS genes in our FALS families that are obtained from (a) spinal cord cDNA library that has been screened against the microdissected chromosome 21q band-specific library and (b) from subtracted cDNA libraries (made from the anterior and posterior gray matter as motor neurons undergo the most profound pathological change and are therefore prime candidate for expression of the FALS gene. Thus, if the FALS gene is represented in our clones, it should map to chromosome 21 and an appropriate polymorphism derived from it should segregate with the disease trait in our FALS families. This may provide a direct approach to the cloning of the FALS gene on Chromosome 21. (4) We have identified a Downs patient with an amyotrophic lateral sclerosis-like syndrome. This patient is a mosaic for trisomy 21, (46XY, normal 21 and marker 21) and a deleted chromosome 21 (46XY, normal 21 and (del)21). We plan to determine the extent of deletion in the deleted chromosome 21 as this may define the limits of the region containing the FALS gene. Yeast artificial chromosomes and cosmids from this region can then be used to generate markers for testing in our families. this robust approach in mapping the chromosome 21 FALS gene will allow its isolation and lead to an understanding of the fundamental defect in the degeneration of motor neurons. This information will be especially useful in formulating a rational treatment of this and related disorders that are otherwise fatal.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Niemann, S; Landers, J E; Churchill, M J et al. (2008) Motoneuron-specific NR3B gene: no association with ALS and evidence for a common null allele. Neurology 70:666-76
Niemann, Stephan; Kanki, Hiroaki; Fukui, Yasuyuki et al. (2007) Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes. Eur J Neurosci 26:1407-20
Morita, M; Al-Chalabi, A; Andersen, P M et al. (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839-44
Francis, J W; Bastia, E; Matthews, C C et al. (2004) Tetanus toxin fragment C as a vector to enhance delivery of proteins to the CNS. Brain Res 1011:7-13
Francis, Jonathan W; Figueiredo, Dayse; vanderSpek, Johanna C et al. (2004) A survival motor neuron:tetanus toxin fragment C fusion protein for the targeted delivery of SMN protein to neurons. Brain Res 995:84-96
Sapp, Peter C; Hosler, Betsy A; McKenna-Yasek, Diane et al. (2003) Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet 73:397-403
Rodriguez, Jorge A; Valentine, Joan S; Eggers, Daryl K et al. (2002) Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase. J Biol Chem 277:15932-7
Hayward, Lawrence J; Rodriguez, Jorge A; Kim, Ji W et al. (2002) Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem 277:15923-31
Aoki, M; Liu, J; Richard, I et al. (2001) Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. Neurology 57:271-8
Nagai, M; Aoki, M; Miyoshi, I et al. (2001) Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease. J Neurosci 21:9246-54

Showing the most recent 10 out of 41 publications