PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations
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)...
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doaj-76f37ba3cc5a4338b06686ff8b6c46272020-11-24T21:51:47ZengMDPI AGJournal of Clinical Medicine2077-03832018-10-0171034210.3390/jcm7100342jcm7100342PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the MutationsNancy C. Cloake0Jun Yan1Atefeh Aminian2Michael P. Pender3Judith M. Greer4UQ Centre for Clinical Research, the University of Queensland, Brisbane, QLD 4029, AustraliaUQ Centre for Clinical Research, the University of Queensland, Brisbane, QLD 4029, AustraliaUQ Centre for Clinical Research, the University of Queensland, Brisbane, QLD 4029, AustraliaFaculty of Medicine, the University of Queensland, Brisbane, QLD 4029, AustraliaUQ Centre for Clinical Research, the University of Queensland, Brisbane, QLD 4029, AustraliaPLP1 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.http://www.mdpi.com/2077-0383/7/10/342myelin proteolipid protein (PLP)multiple sclerosis (MS)point mutationsprimary progressive MSwomenunfolded protein responseepitopes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nancy C. Cloake Jun Yan Atefeh Aminian Michael P. Pender Judith M. Greer |
spellingShingle |
Nancy C. Cloake Jun Yan Atefeh Aminian Michael P. Pender Judith M. Greer PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations Journal of Clinical Medicine myelin proteolipid protein (PLP) multiple sclerosis (MS) point mutations primary progressive MS women unfolded protein response epitopes |
author_facet |
Nancy C. Cloake Jun Yan Atefeh Aminian Michael P. Pender Judith M. Greer |
author_sort |
Nancy C. Cloake |
title |
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations |
title_short |
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations |
title_full |
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations |
title_fullStr |
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations |
title_full_unstemmed |
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations |
title_sort |
plp1 mutations in patients with multiple sclerosis: identification of a new mutation and potential pathogenicity of the mutations |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2018-10-01 |
description |
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. |
topic |
myelin proteolipid protein (PLP) multiple sclerosis (MS) point mutations primary progressive MS women unfolded protein response epitopes |
url |
http://www.mdpi.com/2077-0383/7/10/342 |
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