Human Molecular Genetics Advance Access originally published online on May 25, 2005
Human Molecular Genetics 2005 14(14):1977-1989; doi:10.1093/hmg/ddi203
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Identification of quantitative trait loci controlling cortical motor evoked potentials in experimental autoimmune encephalomyelitis: correlation with incidence, onset and severity of disease
1Department of Immunology and 2Department of Neurology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany, 3Institute of Animal Science, Humboldt University, Berlin, Germany and 4Department of Pathology, Institute of Clinical Pathology, University Hospital Zürich, Switzerland
* To whom correspondence should be addressed. Tel: +49 3814945872; Fax: +49 3814945882; Email: saleh.ibrahim{at}med.uni-rostock.de
Received January 26, 2005; Revised March 24, 2005; Accepted May 23, 2005
Experimental autoimmune encephalomyelitis (EAE) is a polygenic chronic inflammatory demyelinating disease of the nervous system, commonly used as an animal model of multiple sclerosis. Previous studies have identified multiple quantitative trait loci (QTLs) controlling different aspects of disease pathogenesis. However, direct genetic control of cortical motor evoked potentials (cMEPs) as a straightforward measure of extent of demyelination or synaptic block has not been investigated earlier. Here, we examined the genetic control of different traits of EAE in a F2 intercross population generated from the EAE susceptible SJL/J (SJL) and the EAE resistant C57BL/10.S (B10.S) mouse strains involving 400 animals. The genotypes of 150 microsatellite markers were determined in each animal and correlated to phenotypic data of onset and severity of disease, cell infiltration and cMEPs. Nine QTLs were identified. Three sex-linked QTLs mapped to chromosomes 2, 10 and 18 linked to disease severity in females, whereas QTLs on chromosomes 1, 8 and 15 linked to the latency of the cMEPs. QTLs affecting T-lymphocyte, B-lymphocyte and microglia infiltration mapped on chromosomes 8 and 15. The cMEP-associated QTLs correlated with incidence, onset or severity of disease, e.g. QTL on chromosome 8, 32–48 cM (EAE 31) (LOD 6.9, P<0.001), associated to cMEP latencies in non-immunized mice and correlated with disease onset and EAE 32 on chromosome 15 linked to cMEP latencies 15 days post-immunization and correlated with disease severity. Additionally, applying tissue microarray technology, we identified QTLs associated to microglia and lymphocytes infiltration on chromosomes 8 and 15, which are different from the QTLs controlling cMEP latencies. There were no alterations in the morphological appearance of the myelin sheaths. Our findings suggest a possible role of myelin composition and/or synaptic transmission in susceptibility to EAE.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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