title: A missense variant of the ATP1A2 gene is associated with a novel phenotype of progressive sensorineural hearing loss associated with migraine.
abstract: Hereditary sensorineural hearing loss is an extremely clinical and genetic heterogeneous disorder in humans. Especially, syndromic hearing loss is subdivided by combinations of various phenotypes, and each subtype is related to different genes. We present a new form of progressive hearing loss with migraine found to be associated with a variant in the ATP1A2 gene. The ATP1A2 gene has been reported as the major genetic cause of familial migraine by several previous studies. A Korean family presenting progressive hearing loss with migraine was ascertained. The affected members did not show any aura or other neurologic symptoms during migraine attacks, indicating on a novel phenotype of syndromic hearing loss. To identify the causative gene, linkage analysis and whole-exome sequencing were performed. A novel missense variant, c.571G>A (p.(Val191Met)), was identified in the ATP1A2 gene that showed co-segregation with the phenotype in the family. In silico studies suggest that this variant causes a change in hydrophobic interactions and thereby slightly destabilize the A-domain of Na(+)/K(+)-ATPase. However, functional studies failed to show any effect of the p.(Val191Met) substitution on the catalytic rate of this enzyme. We describe a new phenotype of progressive hearing loss with migraine associated with a variant in the ATP1A2 gene. This study suggests that a variant in Na(+)/K(+)-ATPase can be involved in both migraine and hearing loss.
authors.affiliation: 1] Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea [2] School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea.
authors.forename: Se-Kyung
authors.initials: SK
authors.lastname: Oh
authors.affiliation: 1] Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea [2] Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jeong-In
authors.initials: JI
authors.lastname: Baek
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Karl M
authors.initials: KM
authors.lastname: Weigand
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Herman G P
authors.initials: HG
authors.lastname: Swarts
authors.affiliation: Department of Neurosurgery, Kyungpook National University Hospital, Daegu, South Korea.
authors.forename: Seong-Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Hashim Raza
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu, South Korea.
authors.forename: Da Jung
authors.initials: DJ
authors.lastname: Jung
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu, South Korea.
authors.forename: Sang-Heun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Institute of Chemistry, Technical University of Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Friedrich
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
authors.affiliation: 1] Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea [2] School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea [3] Advanced Bio-resource Research Center (ABRC), Kyungpook National University, Daegu, South Korea.
authors.forename: Un-Kyung
authors.initials: UK
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu, South Korea.
authors.forename: Kyu-Yup
authors.initials: KY
authors.lastname: Lee
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D018450:Disease Progression; D059472:Exome; D005799:Genes, Dominant; D008040:Genetic Linkage; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008126:Lod Score; D008297:Male; D008881:Migraine Disorders / Q000175:diagnosis / Q000209:etiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D016415:Sequence Alignment; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase