Genetic analysis of aquaporin-4 in neuromyelitis optica
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.
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COINVESTIGATORS
NMO Genetics Coinvestigators: Wolfgang Kristoferitsch, MD (SMZ-Ost-Donauspital, Vienna, Austria; Site Investigator); Wilfried Lang, MD (Krankenhaus Barmherzige Brueder, Vienna, Austria; Site Investigator); Friedemann Paul, MD (Charite-University Medicine, Berlin, Germany; Site Investigator); Sven Jarius, MD (University of Heidelberg, Heidelberg, Germany; Site Investigator); Anu Jacob, MD, and Mike Boggild, MD (Walton Centre, Liverpool, UK; Site Investigators); Amilton A. Barreira, MD, and Doralina Brum, MD (FMRP-USP, Riberão Preto, SP, Brazil; Site Investigators); Anne Cross, MD, and Laura Piccio, MD (Washington University, St. Louis, MO; Site Investigators); Hollie Schmidt (Accelerated Cure Project, Waltham, MA; Vice President of Scientific Operations); Gareth Parry, MD (University of Minnesota, Minneapolis, MN; Site Investigator); Thomas Scott, MD (Allegheny General Hospital, Pittsburgh, PA; Site Investigator); Gabriel Pardo, MD (OMRF Multiple Sclerosis Center of Excellence, Oklahoma City, OK; Site Investigator); Daniel Mikol, MD, PhD (EMD Serono; Site Investigator).
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Copyright © 2011 by AAN Enterprises, Inc.
Publication History
Received: March 24, 2011
Accepted: May 25, 2011
Published online: September 7, 2011
Published in print: September 20, 2011
Disclosure
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.
Authors
Author Contributions
Marcelo Matiello: study concept and design, obtaining funding, acquisition of data, drafting/revising the manuscript for content. Janet L. Schaefer-Klein: acquisition and analysis of data. David D. Hebrink: acquisition and analysis of data. Daniel J. Kingsbury: acquisition and analysis of data. Elizabeth J. Atkinson: statistical analysis. Brian G. Weinshenker MD: study concept and design, obtaining funding, acquisition of data, drafting/revising the manuscript for content, study supervision and coordination.
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- Thermodynamics and S -Palmitoylation Dependence of Interactions between Human Aquaporin-4 M1 Tetramers in Model Membranes , The Journal of Physical Chemistry B, 128, 3, (603-621), (2024).https://doi.org/10.1021/acs.jpcb.3c04529
- Genetic Factors in Neuroimmune Diseases, Neuroimmune Diseases, (1-31), (2024).https://doi.org/10.1007/978-3-031-24297-7_11-1
- Neuromyelitis Optica Spectrum Disorders: Clinical Perspectives, Molecular Mechanisms, and Treatments, Applied Sciences, 13, 8, (5029), (2023).https://doi.org/10.3390/app13085029
- dbAQP-SNP: a database of missense single-nucleotide polymorphisms in human aquaporins, Database, 2023, (2023).https://doi.org/10.1093/database/baad012
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