ArticleHuman mutation2019
A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.
Open access · greenAbstract readMulticenter Study
In one paragraph
Article in Human mutation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18citing papers in PubMed
1.2field-weighted citation impact, top 23% of its field
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Who cites it
18 citing papers in PubMed, 16 citations in OpenAlex.
- Naming the alpha-2-macroglobulin gene family across vertebrates.Human genomics · 2026Article
- A de Novo 2q23.1-2q23.3 duplication in a neonate with anemia, thrombocytopenia, and hypospadias: clinical and genomic characterization.Molecular cytogenetics · 2025Article
- Multi-omics integration and machine learning uncover molecular basal-like subtype of pancreatic cancer and implicate A2ML1 in promoting tumor epithelial-mesenchymal transition.Journal of translational medicine · 2025Article
- A NovelInternational journal of molecular sciences · 2025Article
- M2 macrophage infiltration drives tumor progression and identifies a multigene prognostic signature in esophageal cancer.Frontiers in immunology · 2025Article
- Identification of rare missense variants in the BSN gene co-segregating with chronic otitis media in a consanguineous Pakistani family.Molecular genetics & genomic medicine · 2024Article
- The A2ml1-Knockout mouse as an animal model for non-syndromic otitis media.International journal of pediatric otorhinolaryngology · 2024Article
- Microbial Metagenomes and Host Transcriptomes Reveal the Dynamic Changes of Rumen Gene Expression, Microbial Colonization and Co-Regulation of Mineral Element Metabolism in Yaks from Birth to Adulthood.Animals : an open access journal from MDPI · 2024Article
- Lack of Methylation Changes inActa medica Philippina · 2023Article
- Audiologic Measures in an Indigenous Community withGenetic testing and molecular biomarkers · 2023Article
- Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.Nature communications · 2022Article
- Otitis media susceptibility and shifts in the head and neck microbiome due toJournal of medical genetics · 2021Article
- Genomic Regions and Candidate Genes Linked to Capped Hock in Pig.Life (Basel, Switzerland) · 2021Article
- TheFrontiers in cellular and infection microbiology · 2021Article
- αThe Journal of biological chemistry · 2020Article
- Panel 2- recent advance in otitis media bioinformatics.International journal of pediatric otorhinolaryngology · 2020Review
- Genomics of Otitis Media (OM): Molecular Genetics Approaches to Characterize Disease Pathophysiology.Frontiers in genetics · 2020Review
- Current Understanding of Host Genetics of Otitis Media.Frontiers in genetics · 2019Review
Corrections and comments
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Authors and funding
54 authors at 15 institutions in 5 countries.
Eric D LarsonDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Jose Pedrito M MagnoDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Matthew J SteritzDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Erasmo Gonzalo D V LlanesDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Jonathan CardwellDepartment of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Melquiadesa PedroPhilippine National Ear Institute, University of the Philippines Manila - National Institutes of Health, Manila, Philippines.
Tori Bootpetch RobertsDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Elisabet EinarsdottirFolkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland.
Rose Anne Q RosanesDepartment of Community Dentistry, College of Dentistry, University of the Philippines Manila, Manila, Philippines.
Christopher GreenleeDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Rachel Ann P SantosNordhoff Craniofacial Center, Manila, Philippines.
Ayesha YousafInstitute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan.
Sven-Olrik StreubelDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Aileen Trinidad R SantosNordhoff Craniofacial Center, Manila, Philippines.
Amanda G RuizDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Sheryl Mae Lagrana-VillagraciaPhilippine National Ear Institute, University of the Philippines Manila - National Institutes of Health, Manila, Philippines.
Dylan RayDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Talitha Karisse L YarzaPhilippine National Ear Institute, University of the Philippines Manila - National Institutes of Health, Manila, Philippines.
Melissa A ScholesDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Catherine B AndersonDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Anushree AcharyaCenter for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
University of Washington Center for Mendelian Genomics
Samuel P GubbelsDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Michael J BamshadDepartment of Genome Sciences, University of Washington, Seattle, Washington.
Stephen P CassDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Nanette R LeeUSC-Office of Population Studies Foundation, Inc. and Department of Anthropology, Sociology and History, University of San Carlos, Cebu, Philippines.
Rehan S ShaikhInstitute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan.
Deborah A NickersonDepartment of Genome Sciences, University of Washington, Seattle, Washington.
Karen L MohlkeDepartment of Genetics, University of North Carolina, Chapel Hill, North Carolina.
Jeremy D PragerDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Teresa Luisa G CruzDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Patricia J YoonDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Generoso T AbesDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
David A SchwartzDepartment of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Abner L ChanDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Todd M WineDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Eva Maria Cutiongco-de la PazPhilippine Genome Center, University of the Philippines, Quezon City, Philippines.
Norman FriedmanDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Katerina KechrisDepartment of Biostatistics and Bioinformatics, Colorado School of Public Health, Aurora, Colorado.
Juha KereFolkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland.
Suzanne M LealCenter for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Ivana V YangDepartment of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Janak A PatelDivision of Infectious Diseases, Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas.
Ma Leah C TantocoDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Saima RiazuddinDepartment of Otorhinolaryngology, Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland.ORCID 0000-0002-8645-4761
Kenny H ChanDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Petri S MattilaDepartment of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Maria Rina T Reyes-QuintosDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Zubair M AhmedDepartment of Otorhinolaryngology, Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
Herman A JenkinsDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.
Tasnee ChonmaitreeDivision of Infectious Diseases, Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas.
Lena HafrénDepartment of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Charlotte M ChiongDepartment of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines.
Regie Lyn P Santos-CortezDepartment of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.ORCID 0000-0002-9958-2535
Philippine General Hospital · PHUniversity of Colorado Denver · USUniversity of Helsinki · FIChildren's Hospital Colorado · USUniversity of Maryland, Baltimore · USUniversity of the Philippines Manila · PHBahauddin Zakariya University · PKBaylor College of Medicine · USInternational Craniofacial Institute · USThe University of Texas Medical Branch at Galveston · USUniversity of North Carolina at Chapel Hill · USUniversity of the Philippines System · PHUniversity of Washington · USColorado School of Public Health · USUniversity of San Carlos · PH
Funding
UW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MOtitis Media Susceptibility and Middle Ear Microbial Shifts due to Gene VariantsR01DC015004 · NIDCD · UNIVERSITY OF COLORADO DENVER · PI SANTOS-CORTEZ, REGIE LYN PASTOR · 2016 to 2020
$1.9MIdentifying Genes for Non-Syndromic Recessive Deafness-A Collaborative StudyR56DC011803 · NIDCD · UNIVERSITY OF MARYLAND BALTIMORE · PI RIAZUDDIN, SAIMA · 2017 to 2017
$638kNHGRI NIH HHS U24 HG008956NHGRI NIH HHS UM1 HG006493NIDCD NIH HHS R01 DC015004NIDCD NIH HHS R56 DC011803Philippine Council for Health Research and Development - Department of Science and Technology Balik Scientist ProgramPhilippine Council for Health Research and Development - Department of Science and Technology FP 150010
Abstract
A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.
Indexed as
Down-RegulationMutationAdolescentAdultalpha-MacroglobulinsChildChild, PreschoolFemaleFinlandGene Expression ProfilingGene Expression RegulationGenetic Predisposition to DiseaseHumansInfantMaleMiddle AgedA2ML1 protein, humanalpha-MacroglobulinsA2ML1alpha-2-macroglobulin-like-1exome sequencingotitis mediaRNA-sequencing
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