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Abstract
Objective: Autoantibodies to aquaporin-4 (AQP4) are specific and pathogenic for neuromyelitis optica (NMO). Therefore, we evaluated whether AQP4 single-nucleotide polymorphisms (SNPs) are associated with susceptibility to NMO or whether mutations that potentially alter AQP4 structure or expression are present in some patients.
Methods: We genotyped 8 AQP4 SNPs chosen based on their minor allele frequency, location, and novelty in 177 NMO sporadic cases, 14 NMO familial cases, and 1,363 matched controls by TaqMan-based assay. We performed bidirectional sequencing of the promoter (1 kb), exons 0–4, and flanking splice consensus sequences, and the 5′ and 3′ untranslated regions of 177 sporadic and 14 familial NMO cases.
Results: One of 8 SNPs (minor allele frequency = 0.01) was associated with NMO (NC 18.8; chrom pos. 22695167: T>A): odds ratio (95% confidence interval) = 13.1 (1.4–126.7); p = 0.026. In 3 patients with NMO (2 related), we detected 2 different missense allelic mutations at Arg19 (R19I and R19T). None of the 1,363 control subjects had Arg19 mutations (p = 0.001).
Conclusions: Except for one uncommon SNP, no tested SNP was associated with NMO, nor were 3 SNP haplotypes, providing no support for the hypothesis that genetic variation in AQP4 accounts for overall susceptibility to NMO. Two different allelic Arg19 missense mutations are specific to NMO and segregated with the disease in one pedigree. Although the pathobiology underlying this is not yet established, their effects on the structure of the M1 isoform N terminus or the regulatory sequence of the M23 isoform by virtue of their location support a role of AQP4 orthogonal array formation on molecular susceptibility to NMO.
Glossary
- GLOSSARY
- AQP4=
- aquaporin-4;
- IgG=
- immunoglobulin G;
- LETM=
- longitudinally extensive spinal cord lesion;
- MS=
- multiple sclerosis;
- NMO=
- neuromyelitis optica;
- OAP=
- orthogonal array particle;
- SNP=
- single-nucleotide polymorphism
Footnotes
-
Study funding: Supported by the Guthy-Jackson Charitable Foundation, a pilot grant from the National MS Society, and the Mayo Clinic CTSA (Grant 1 UL1 RR024150 from the National Center for Research Resources).
-
Supplemental data at www.neurology.org
- Received March 24, 2011.
- Accepted May 25, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
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