The function of gene body DNA methylation in alternative splicing, and its relation
to disease pathogenesis is not fully elucidated. The gene for familial Mediterranean
fever (MEFV) encodes the pyrin protein and contains a 998 bp CpG
island, covering the second exon, which is differentially methylated in FMF patients
compared to healthy controls. Our further observation of increased exon 2-spliced
MEFV transcript in leukocytes of FMF patients provoked us to test
the role of exon methylation in alternative splicing using inflammatory cell culture
models. First, in vitro exon methylation triggered an increased
level of exon 2 exclusion using a splicing cassette in a promyelocytic leukemia cell
line (HL-60). HL-60 cells subjected to methylating and demethylating agents, as well
as cells differentiated to neutrophil-like cells, exhibited different levels of
spliced/unspliced transcripts. We observed increased levels of spliced transcripts in
neutrophil-like (p = 0.0005), activated (p = 0.0034) and methylated cells (p <
0.0001), whereas decreased levels in demethylated cells (p = 0.0126) compared to
control untreated HL-60 cells. We also showed that the protein isoform of pyrin
lacking the exon 2 has an adverse subcellular localization in neutrophil-like cells.
Therefore, it remains in the cytoplasm rather than the nucleus. This may point to an
epigenetic involvement in an important inflammatory gene.
Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified; however, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the presence of a higher rare risk variation burden in the families. In line with this, score distributions among affected and unaffected family members within individual families showed that known susceptibility alleles can explain disease development in some high-risk multiplex families, while in others, additional genetic contributors increase MS risk.
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