Johnson M R, Ferner R E, Bobrow M, Hughes R A
Department of Clinical Neurosciences, Guy's Kings and St Thomas' School of Medicine, Hodgkin Building, Guy's Hospital, London SE1 9RT, UK.
J Neurol Neurosurg Psychiatry. 2000 May;68(5):643-6. doi: 10.1136/jnnp.68.5.643.
Neurofibromatosis 1 (NF1) is a common autosomal disorder with a wide range of neurological manifestations. The case histories of five patients, including two siblings, are reported who have both neurofibromatosis 1 and primary progressive multiple sclerosis (PPMS). A further patient with both NF1 and PPMS has since been identified. More recently, a systematic clinical review of 138 unselected adult patients with NF1 identified one patient with a slowly progressive spastic paraparesis and multiple high signal hyperintensities 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 glycoprotein (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 myelination. It can be detected immunohistochemically on CNS myelin and on the surface of cultured oligodendrocytes. Structurally, OMgp has the potential to function as an adhesion molecule and could contribute to the interactions between the plasma membranes of oligodendrocytes and axons required for myelination and/or axon survival. This study considers the specific hypothesis that 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 examined using a combination of Southern blot, dosage polymerase chain reaction, and chemical cleavage of mismatch. The entire OMgp coding sequence, all intronic sequence, the intron-exon boundaries, and 1 kb of flanking sequence were screened. The DNA from two patients was found to contain an alteration 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.
神经纤维瘤病1型（NF1）是一种常见的常染色体疾病，具有广泛的神经学表现。本文报告了5例患者的病例史，其中包括2例兄弟姐妹，他们同时患有神经纤维瘤病1型和原发性进行性多发性硬化症（PPMS）。此后又确诊了1例同时患有NF1和PPMS的患者。最近，一项对138例未经挑选的成年NF1患者进行的系统临床评估发现，1例患者出现缓慢进展的痉挛性截瘫，T2加权磁共振成像（MRI）显示多处高信号高强度区。分子遗传学研究提示了一种可能导致进行性白质疾病与NF1临床关联的机制。NF1基因位于17号染色体q臂，跨越350 kb的基因组DNA，包含60个外显子。少突胶质细胞髓鞘糖蛋白（OMgp）基因嵌于NF1基因的第27b内含子中。OMgp是一种膜糖蛋白，在髓鞘形成时出现在人类中枢神经系统中。可通过免疫组织化学方法在中枢神经系统髓鞘及培养的少突胶质细胞表面检测到它。从结构上看，OMgp有可能作为一种黏附分子发挥作用，并可能参与少突胶质细胞膜与髓鞘形成和/或轴突存活所需轴突之间的相互作用。本研究探讨了一个特定假说，即NF1患者的PPMS是由OMgp基因的并发突变所致。使用Southern印迹法、剂量聚合酶链反应和错配化学切割相结合的方法，检测了4例无关的NF1和PPMS患者的OMgp基因。对整个OMgp编码序列、所有内含子序列、内含子 - 外显子边界以及1 kb的侧翼序列进行了筛查。发现2例患者的DNA中OMgp基因存在改变，导致第21密码子处的氨基酸由甘氨酸变为天冬氨酸。得出的结论是，NF1患者的PPMS可能在没有OMgp基因并发突变的情况下发生。第21密码子处甘氨酸到天冬氨酸的多态性改变对于PPMS的发生既非充分条件也非必要条件。
