TY - JOUR
T1 - Genetic analysis of aquaporin-4 in neuromyelitis optica
AU - Matiello, M.
AU - Schaefer-Klein, J. L.
AU - Hebrink, D. D.
AU - Kingsbury, D. J.
AU - Atkinson, E. J.
AU - Weinshenker, B. G.
N1 - Funding Information:
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).
Funding Information:
Dr. Matiello is supported by a postdoctoral fellowship grant from the National MS Society. J.L. Schaefer-Klein, D.D. Hebrink, Dr. Kingsbury, and E.J. Atkinson report no disclosures. Dr. Weinshenker serves on data safety monitoring boards for Novartis and Biogen Idec; serves on the editorial boards of the Canadian Journal of Neurological Sciences, the Turkish Journal of Neurology, and Multiple Sclerosis; has received research support from Genzyme Corporation and the Guthy-Jackson Charitable Foundation; and receives license royalties from RSR Ltd. for a patent re: Aquaporin-4 associated antibodies for diagnosis of neuromyelitis optica.
PY - 2011/9/20
Y1 - 2011/9/20
N2 - 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 toNMOor 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.
AB - 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 toNMOor 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.
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U2 - 10.1212/WNL.0b013e31822f045b
DO - 10.1212/WNL.0b013e31822f045b
M3 - Article
C2 - 21900637
AN - SCOPUS:80555143056
SN - 0028-3878
VL - 77
SP - 1149
EP - 1155
JO - Neurology
JF - Neurology
IS - 12
ER -