PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations

Abstract

PLP1 is located on the X-chromosome and encodes myelin proteolipid protein (PLP), the most abundant protein in central nervous system myelin. Generally, point mutations in PLP1 result in X-linked dysmyelinating disorders, such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2). However, several case studies have identified patients with missense point mutations in PLP1 and clinical symptoms and signs compatible with a diagnosis of multiple sclerosis (MS). To investigate if PLP1 mutations occur relatively frequently in MS, we sequenced the coding regions of PLP1 in 22 female MS patients who had developed disease after the age of 40 and in 42 healthy women, and identified a missense mutation in exon 2 of PLP1 resulting in a Leu30Val mutation in the protein in one of the MS patients. mCherry-tagged plasmids containing wild type or mutant PLP1 sequences of PLP, including two known PMD/SPG2-related mutations as positive controls, were constructed and transfected into Cos-7 cells. In comparison with cells transfected with wild type PLP1, all mutations caused significant accumulation of PLP in the endoplasmic reticulum of the cells and induction of the unfolded protein response—a mechanism that leads to apoptosis of cells expressing mutant proteins. Additionally, in silico analysis of the binding of peptides containing the Leu30Val mutation to the human leukocyte antigen (HLA) molecules carried by the patient harboring this mutation suggested that the mutation could produce several novel immunogenic epitopes in this patient. These results support the idea that mutations in myelin-related genes could contribute to the development of MS in a small proportion of patients.

SeXX Matters in Multiple Sclerosis

“…Historically, it was argued that sex differences in MS are primarily due to sex hormones. Nonetheless, emerging evidence demonstrates that sex differences may also be mediated by mechanisms other than hormones, and in particular, by X and/or Y chromosome gene products ( 134 – 139 , 141 , 261 , 262 ). Possibly, genes on the X and Y chromosomes contribute to MS susceptibility and progression in a polygenic fashion.…”

“…Thus, the X chromosome has become a research topic of great interest, and many studies recently sought to understand the role of X-linked genes in the development and progression of MS and generally immune-mediated diseases ( 257 ). Notably, three X chromosome candidate genes have been at the forefront of genetic association studies in MS: PLP (located on Xq22) ( 134 ), cytochrome b-245 β chain (CYBB or NOX2, Xp21) ( 263 ), and gamma-aminobutyric acid ionotropic type A receptor (GABRA3, Xq28) ( 135 ). Although these studies did produce some evidence for association with MS, none of these genes was actually identified in genome-wide association studies (GWAS) ( 264 , 265 ).…”

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

“…Although genetic mutations of myelin proteins as well as traumatic brain injury-associated dysmyelination have been linked to later development of MS, it is not yet clear what initially triggers citrullination of myelin proteins or subtle dysmyelination (Warshawsky et al, 2005;Donovan et al, 2014;Sidaway, 2017;Cloake et al, 2018).…”

Anti-Myelin Proteolipid Protein Peptide Monoclonal Antibodies Recognize Cell Surface Proteins on Developing Neurons and Inhibit Their Differentiation

“…PLP is primarily a myelin structural protein but the plp1 gene products, PLP and DM20 have additional roles in oligodendrocytes and neurons (21–24). Mutations of plp1 cause the X-linked dysmyelinating disorders Pelizaeus-Merzbacher disease and spastic paraplegia type 2 in humans (25), and several recent studies have implicated plp1 mutations in the pathogenesis of MS in some patients (26, 27). Although PLP sequences are identical among mammals and pgf proteins are highly conserved in all vertebrate species, little is known about neuronal expression, distribution, and functions of PLP epitopes or of other pgf proteins in the immature and mature human CNS and how they may relate to the pathogenesis of human CNS diseases.…”