Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic vari...

Full description

Saved in:

Bibliographic Details
Published in:	International journal of molecular sciences 2022-10, Vol.23 (19), p.11461
Main Authors:	Horjus, Julia, van Mourik-Banda, Tineke, Heerings, Marco A. P., Hakobjan, Marina, De Witte, Ward, Heersema, Dorothea J., Jansen, Anne J., Strijbis, Eva M. M., de Jong, Brigit A., Slettenaar, Astrid E. J., Zeinstra, Esther M. P. E., Hoogervorst, Erwin L. J., Franke, Barbara, Kruijer, Wiebe, Jongen, Peter J., Visser, Leo J., Poelmans, Geert
Format:	Article
Language:	eng
Subjects:	Animal models Biological activity Central nervous system Cytokines Demyelination Disease Genes Genetic diversity genetics Genome-wide association studies Genomes Health risk assessment Immunity MeCP2 protein Methyl-CpG binding protein Molecular modelling Multiple sclerosis multiple sclerosis (MS) Myelination Polo-like kinase 1 Proteins Risk analysis Risk factors whole exome sequencing
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.
ISSN:	1422-0067 1661-6596 1422-0067