Detailed analysis of the oligodendrocyte myelin glycoprotein gene in four patients with neurofibromatosis 1 and primary progressive multiple sclerosis

Neurofibromatosis 1 (NF1) is a common autosomal disorder with a wide range of neurological manifestations. The case histories of five patients, includ ing two siblings, are reported who have both neurofibromatosis 1 and primar y progressive multiple sclerosis (PPMS). A further patient with both NF1 an d PPMS has since been identified. More recently, a systematic clinical revi ew of 138 unselected adult patients with NF1 identified one patient with a slowly progressive spastic paraparesis and multiple high signal hyperintens ities on T2 weighted MRI. Molecular genetic studies suggest a mechanism by which the clinical association of progressive white matter disease and NF1 might arise. The gene for NF1 is located on chromosome 17q, spans 350 kb of genomic DNA, and contains 60 exons. The gene for oligodendrocyte myelin gl ycoprotein (OMgp) is embedded within intron 27b of the NF1 gene. OMgp is a membrane glycoprotein that appears in the human CNS at the time of myelinat ion. It can be detected immunohistochemically on CNS myelin and on the surf ace of cultured oligodendrocytes. Structurally, OMgp has the potential to f unction as an adhesion molecule and could contribute to the interactions be tween the plasma membranes of oligodendrocytes and axons required for myeli nation and/or axon survival. This study considers the specific hypothesis t hat PPMS in patients with NF1 results from concurrent mutation of the OMgp gene. The OMgp genes of four unrelated patients with NF1 and PPMS were exam ined using a combination of Southern blot, dosage polymerase chain reaction , and chemical cleavage of mismatch. The entire OMgp coding sequence, all i ntronic sequence, the intron-exon boundaries, and 1 kb of flanking sequence were screened. The DNA from two patients was found to contain an alteratio n in the OMgp gene resulting in an amino acid change of glycine to aspartic acid at codon 21. It is concluded that PPMS in patients with NF1 can occur without concurrent mutation of the OMgp gene. The glycine to aspartic acid polymorphic alteration at codon 21 is neither sufficient nor necessary for the development of PPMS.