Multiple sclerosis in a radiosensitive family with low levels of the ATM protein.
Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system (CNS) characterized by demyelination associated with progressive disability. The mechanisms underlying the pathogenesis of MS remain a mystery. The highly pleiotropic syndrome known as ataxia telangiectasia (A-T) overlaps with MS in that it also presents with demyelination in the CNS. Whether demyelination in MS or in A-T is initiated through neuronal degeneration or immune dysfunction is not yet known. However, unlike MS, the underlying cause of A-T is known to result from mutations in the A-T gene (ATM) that often result in the complete loss of ATM protein and loss/gain of function. ATM is implicated in neurological degeneration, particularly in the cerebellum, cellular apoptosis, immunodeficiency, double stranded deoxyribonucleic acid (DNA) rejoining, VDJ antibody recombination, tumour suppression, particularly T-lymphoid malignancies, signal transduction, cell-cycle control and cellular radiohypersensitivity. In this study, we describe a case of MS in a family with cellular radiosensitivity and abnormally low postinduction levels of the ATM protein. Defective DNA repair/rejoining may impact on autoimmunity.
Division of Cancer Services, The St George Hospital, University of New South Wales, Australia. R.Clarke@unsw.edu.au
Raymond A
RA
Clarke
Zhi M
ZM
Fang
Cheok S
CS
Lee
Maria
M
Sarris
Dédée
D
Murrell
John H
JH
Kearsley
D000328:Adult; D000368:Aged; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D015551:Autoimmunity; D001706:Biopsy; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011836:Radiation Tolerance; D012867:Skin / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases