Gene polymorphism at position -308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and it's influence on the regulation of TNF-alpha production.
Tumor-necrosis-factor alpha (TNF-alpha) is a major mediator of the inflammatory immune response and may play an important role in the pathogenesis and progression of Multiple Sclerosis (MS). Increased TNF-alpha levels of cerebrospinal fluid (CSF) and peripheral blood were found in patients with chronic progressive MS and patients with acute relapses, but not in the stable form of the disease. Considering the association of different TNF-alpha alleles with diverse autoimmune diseases we sequenced the TNF-alpha promotor region (-674 to +201) of 23 patients with relapsing/remitting MS, of 27 patients with chronic progressive MS (21 patients had primary progressive course and six patients had a secondary progressive course) and of 22 healthy controls, who had no history of MS in their families. In three of 21 patients (14%) with primary chronic progressive MS a homozygous point-mutation at position -308 could be demonstrated where guanine (G) was substituted by adenosine (A). This mutation could neither be detected in patients with relapsing/remitting MS nor in healthy controls. However, 40% of the patients with relapsing/remitting MS and 43% of the primary chronic progressive MS patients were heterozygous at position -308 for G/A, whereas only 32% of healthy controls showed this heterogeneity. The genetic variations were demonstrated by polymerase chain reaction (PCR)-amplification of the TNF-alpha promotor-region and consecutive direct automatic sequencing. Functional analysis of the promoter region using the chloramphenicol-acetyltransferase (CAT) assay revealed spontaneous production with the homozygous mutation at -308 only.
Department of Neurology, University of Würzburg, Germany.
N
N
Braun
U
U
Michel
B P
BP
Ernst
R
R
Metzner
A
A
Bitsch
F
F
Weber
P
P
Rieckmann
D000241:Adenosine; D000328:Adult; D000483:Alleles; D003001:Cloning, Molecular; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006147:Guanine; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D006147:Guanine; D000241:Adenosine