DOI: 10.4225/03/5897b936b9f33
title: Exploring genetic variation in multiple sclerosis

description: Recent genome wide association studies (GWAS) into factors influencing multiple sclerosis 
(MS)  have  uncovered  loci  that  affect  susceptibility  to  multiple  sclerosis.  These  discoveries 
add  to  existing  evidence  that  genetic  factors  are  important  in  MS.  The  work  in  this  thesis 
continues  investigation  of  the  mechanisms  in  which  some  of  these  genetic  factors  may 
influence susceptibility to MS, and the relationship between MS susceptibility and severity.  
 
The myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed 
exclusively  in  oligodendrocytes.  Peptides  from  the  MOG  protein  sequence  can  induce  an 
acute, central nervous system (CNS) restricted autoimmune condition in susceptible animals 
called experimental autoimmune encephalomyelitis (EAE) which resembles some aspects of 
MS.  Candidate  gene  studies  have  been  equivocal  in  suggesting  a  role  for  MOG  in  MS, 
however  a  recent,  large  study  supports  an  association  between  a  polymorphism  in  MOG 
(rs3130253)  and  susceptibility  to  MS.  These  studies  demonstrate  that  the  MS-associated 
polymorphism is associated with changes in the processing of the MOG pre-mRNA transcript 
that  favour  an  increase  in  exon  2  to  exon  3  splicing.  A  plausible  outcome  from  increased 
exon 2/3 splicing of the MOG pre-mRNA is increased expression of MOG protein isoforms  
containing  exons  1–3,  which  includes the  extracellular and  transmembrane  domains,  on  
the  surface  of oligodendrocytes. As the extracellular domain in an important epitope in MS 
and EAE, an alteration in the expression of MOG protein may affect MS susceptibility. 
 
C-type  lectin  family  16,  member  A  (CLEC16A)  is  a  gene  that  has  been  associated  with 
susceptibility to MS and to other autoimmune diseases. Beyond these associations, very little 
is  known  about  this  gene.  The  data  in  this  thesis  provides  a  basic  characterisation  of  the 
molecular  biology  of  CLEC16A.  This  thesis  demonstrates  that  there  is  brain-tissue  specific 
splicing  of  CLEC16A  pre-mRNA  that  is  conserved  between  the  mouse  and  the  human; 
however    no    differences    in    splicing    were    correlated    with    the    disease-associated 
polymorphisms in brain tissue. A yeast-2-hybrid screen against a mouse cortical library found 
that the FPL domain of  CLEC16A interacted with HGF-regulated tyrosine kinase substrate 
(Hrs) and Alix, members of the endosomal sorting complex required for transport (ESCRT) 
pathway, involved in sorting and trafficking proteins to the late endosome and lysosome. The 
studies  regarding  CLEC16A  presented  in  this  thesis  contribute  to  the  knowledge  about  the 
biology of CLEC16A, and suggest a function for the protein.   
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There is potential that recently discovered genetic susceptibility factors could modulate MS 
disease  severity,  as  demonstrated  previously  for  the  MS  risk  allele  HLA-DR15.  This 
hypothesis was investigated in a cohort of 1006 well characterised MS patients from South-
Eastern Australia. SNPs from seven loci (CLEC16A, IL2RA, IL7R, EVI5/RPL5, CD58, CD40 
and  chromosome  12q13-14)  were  assessed  for  association  with  five  measures  of  disease 
severity incorporating disability, age of onset,  cognition and brain atrophy. Trends towards 
association  were  observed  between  the  EVI5/RPL5  risk  SNP  and  time  between  first 
demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. 
No  associations  were  significant  after  correction  for  multiple  testing.  This  data  does  not 
provide  evidence  for  the  hypothesis  that  these  MS  disease  risk-associated  SNPs  influence 
disease severity. 
 
Collectively,  the  data  presented  in  this  thesis  explores  some  aspects  of  genetic  variation  in 
MS.