A2ML1 and otitis media : novel variants, differential expression, and relevant pathways

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Larson , E D , Magno , J P M , Steritz , M J , Llanes , E G D , Cardwell , J , Pedro , M , Roberts , T B , Einarsdottir , E , Rosanes , R A Q , Greenlee , C , Santos , R A P , Yousaf , A , Streubel , S-O , Santos , A T R , Ruiz , A G , Mae Lagrana-Villagracia , S , Ray , D , Yarza , T K L , Scholes , M A , Anderson , C B , Acharya , A , Gubbels , S P , Bamshad , M J , Cass , S P , Lee , N R , Shaikh , R S , Nickerson , D A , Mohlke , K L , Prager , J D , Cruz , T L G , Yoon , P J , Abes , G T , Schwartz , D A , Chan , A L , Wine , T M , Maria Cutiongco-de la Paz , E , Friedman , N , Kechris , K , Kere , J , Leal , S M , Yang , I , Patel , J A , Tantoco , M L C , Riazuddin , S , Chan , K H , Mattila , P S , Reyes-Quintos , M R T , Ahmed , Z M , Jenkins , H A , Chonmaitree , T , Hafren , L , Chiong , C M & Santos-Cortez , R L P 2019 , ' A2ML1 and otitis media : novel variants, differential expression, and relevant pathways ' , Human Mutation , vol. 40 , no. 8 , pp. 1156-1171 . https://doi.org/10.1002/humu.23769

Title: A2ML1 and otitis media : novel variants, differential expression, and relevant pathways
Author: Larson, Eric D.; Magno, Jose Pedrito M.; Steritz, Matthew J.; Llanes, Erasmo Gonzalo d; Cardwell, Jonathan; Pedro, Melquiadesa; Roberts, Tori Bootpetch; Einarsdottir, Elisabet; Rosanes, Rose Anne Q.; Greenlee, Christopher; Santos, Rachel Ann P.; Yousaf, Ayesha; Streubel, Sven-Olrik; Santos, Aileen Trinidad R.; Ruiz, Amanda G.; Mae Lagrana-Villagracia, Sheryl; Ray, Dylan; Yarza, Talitha Karisse L.; Scholes, Melissa A.; Anderson, Catherine B.; Acharya, Anushree; Gubbels, Samuel P.; Bamshad, Michael J.; Cass, Stephen P.; Lee, Nanette R.; Shaikh, Rehan S.; Nickerson, Deborah A.; Mohlke, Karen L.; Prager, Jeremy D.; Cruz, Teresa Luisa G.; Yoon, Patricia J.; Abes, Generoso T.; Schwartz, David A.; Chan, Abner L.; Wine, Todd M.; Maria Cutiongco-de la Paz, Eva; Friedman, Norman; Kechris, Katerina; Kere, Juha; Leal, Suzanne M.; Yang, Ivana; Patel, Janak A.; Tantoco, Ma Leah C.; Riazuddin, Saima; Chan, Kenny H.; Mattila, Petri S.; Reyes-Quintos, Maria Rina T.; Ahmed, Zubair M.; Jenkins, Herman A.; Chonmaitree, Tasnee; Hafren, Lena; Chiong, Charlotte M.; Santos-Cortez, Regie Lyn P.
Contributor: University of Helsinki, University Management
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, HUS Head and Neck Center
University of Helsinki, Clinicum
Date: 2019-08
Language: eng
Number of pages: 16
Belongs to series: Human Mutation
ISSN: 1059-7794
URI: http://hdl.handle.net/10138/312957
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.
Subject: A2ML1
exome sequencing
otitis media
1184 Genetics, developmental biology, physiology

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