C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients

Abstract

In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association ( p -value ≤ 5 × 10 -6 ). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) ≤ 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 × 10 -7 and p < 1 × 10 -20 ). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3′ region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS.

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

“…In a targeted study of low-frequency variants in MS of Italian families, followed by studies in a cohort of 120 unrelated MS patients, statistically significant differences were observed in the comparison with control subjects for rs7201683. This SNP causes a p.Leu216Val missense variation in WWOX [ 71 ]. Recently, an additional variant mapping to the WWOX locus has been identified in another large-scale population-based study of 47,429 MS patients and 68,374 control subjects.…”

Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes

“…Our current observations do not imply that WWOX expression in other brain cell types, such as astrocytes and oligodendrocyte, are dispensable. Evidence linking WWOX function with oligodendrocyte pathology is starting to emerge (International Multiple Sclerosis Genetics C, 2019 ; International Multiple Sclerosis Genetics C et al , 2013 ; Jakel et al , 2019 ; Matsushita et al , 2015 ; Ziliotto et al , 2019 ); however, less is known about the cell‐autonomous functions of WWOX in oligodendrocytes. The fact that WWOX expression in neurons regulates oligodendrocyte maturation and antagonizes astrogliosis (Hussain et al , 2019 ) suggests a complex function of WWOX in CNS physiology and pathophysiology that warrants further in‐depth analysis.…”

Neonatal neuronal WWOX gene therapy rescuesWwoxnull phenotypes

“…10,43,44 Our current observations do not imply that WWOX expression in other brain cell types, such as astrocytes and oligodendrocyte, are dispensable. Evidence linking WWOX function with oligodendrocyte pathology is starting to emerge [45][46][47][48][49] , however less is known about the cell-autonomous functions of WWOX in oligodendrocytes. The fact that WWOX expression in neurons regulates oligodendrocyte maturation and antagonizes astrogliosis 50 suggests a complex function of WWOX in CNS physiology and pathophysiology that warrants further in-depth analysis.…”