Myelin oligodendrocyte glycoprotein polymorphisms and multiple sclerosis

Abstract

A detailed analysis of the coding sequences of myelin oligodendrocyte glycoprotei (MOG) gene was performed in multiple sclerosis (MS) patients and in control individuals and three new polymorphisms are described: T636C, nt 571+77C→T (IVS 4), and nt 710−44A→G (IVS 6). Screening studies demonstrated that T636C was present in three MS patients and in no control individual and that polymorphisms nt 571+77C→T (IVS 4), and nt 710−44A→G (IVS 6), were present with no significant frequency differences in MS patients and control individuals. No mutations were found after sequencing the coding sequences of the extracellular domain of MOG gene in 20 MS patients and 20 control individuals. Screening studies were also performed for known polymorphisms: G15A, Val142Leu, nt 571+68A→G (IVS 4), and 571+92C→G (IVS 4). Polymorphism Val 142 Leu, which is linked to nt 571+68A→G (IVS 4), resulted under-represented in MS patients.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is the most frequent chronic neurological disorder affecting young adults. The population prevalence of multiple sclerosis is 0.1%. However, the risk of the disease in the siblings of affected individuals is much higher at 3–5%. The etiology of disease in still unknown, but there is evidence indicating that MS is an autoimmune multifactorial disease with a complex mode of inheritance.

Despite extensive efforts to identify the major genes influencing disease susceptibility, the only region clearly associated with MS is the major histocompatibility complex (MHC). This association, however, accounts just in part for the general MS susceptibility, and probably many other genes are involved. Genomewide screens of MS families have provided several provisional sites, but only three chromosomal regions, 6p21, 5p, and 17q22, were positive in more than one data set (for review, see Noseworthy, 1999). Beside the HLA complex, the 6p21 region contains more than 30 genes directly involved in the immune response, among which the gene coding for the myelin oligodendrocyte glycoprotein (MOG). MOG, a member of the immunoglobulin superfamily, is a quantitatively minor specific CNS component of myelin and may be a target for antibody-induced demyelination. Anti-MOG antibodies are indeed sufficient to cause demyelination in vitro and in experimental animals (Johns and Bernard, 1999). The restricted localization of MS lesions to the CNS white matter and the fact that MOG is a myelin specific CNS component make it possible to hypothesized that MOG could influence MS susceptibility as a primary target for autoimmune response. Furthermore, it has been reported by Kerlero de Rosbo et al. (1997) that T cell response to MOG differs markedly between MS patients and control individuals, suggesting a strong association between autoreactivity to MOG and MS.

Although MOG is an attractive candidate for being involved in MS susceptibility, until now data aiming to demonstrate an association between MOG polymorphisms and susceptibility to MS have been inconsistent. Polymorphic tri- and tetranucleotide repeats (Malfroy et al., 1995), three microsatellites; two located upstream of the MOG gene and one located in intron 2 (Roth et al., 1995), and a polymorphism that causes the substitution of valine for isoleucine at position 145 in exon 3 (Rodriguez et al., 1997), have been described, but comparison of allelic frequencies between controls and MS patients has not shown significant differences or the differences seen in one populations have not been confirmed in other ethnic groups. A Taq I RFLP has been found to be associated to MS in an Australian population (Hilton et al., 1995), but seemingly the same RFLP resulted not MS-associated in a population from the Southampton area (Brown et al., 1998).

A more detailed analysis of the MOG gene is clearly necessary to determine if alterations in this gene influence susceptibility to MS.

We report three new polymorphisms of the MOG gene. The frequency of these sequence variations and the frequency of other four MOG polymorphisms recently described by our group (Gomez-Lira et al., 2000) were investigated in MS patients and in control individuals of the same northern Italian population.