Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in humans, yet the molecular etiology is currently unknown. Evidence suggests that genetic factors may play an important role in some cases of idiopathic BPPV, particularly in familial cases, but the responsible genetic...

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Autores principales:	Yinfang Xu, Yan Zhang, Ivan A Lopez, Jacey Hilbers, Anthony J Griswold, Akira Ishiyama, Susan Blanton, Xue Zhong Liu, Yunxia Wang Lundberg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/38c2bbb8d12249e78cb682cf7cdeecd5
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spelling	oai:doaj.org-article:38c2bbb8d12249e78cb682cf7cdeecd52021-11-25T06:19:17ZIdentification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.1932-620310.1371/journal.pone.0251386https://doaj.org/article/38c2bbb8d12249e78cb682cf7cdeecd52021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0251386https://doaj.org/toc/1932-6203Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in humans, yet the molecular etiology is currently unknown. Evidence suggests that genetic factors may play an important role in some cases of idiopathic BPPV, particularly in familial cases, but the responsible genetic variants have not been identified. In this study, we performed whole exome sequencing [including untranslated regions (UTRs)] of 12 families and Sanger sequencing of additional 30 families with recurrent BPPV in Caucasians from the United States (US) Midwest region, to identify the genetic variants responsible for heightened susceptibility to BPPV. Fifty non-BPPV families were included as controls. In silico and experimental analyses of candidate variants show that an insertion variant rs113784532 (frameshift causing truncation) in the neural cadherin gene PCDHGA10 (protocadherin-gamma A10) is an exceedingly strong candidate (p = 1.80x10-4 vs. sample controls; p = 5.85x10-19 vs. ExAC data; p = 4.9x10-3 vs. NHLBI exome data). The mutant protein forms large aggregates in BPPV samples even at young ages, and affected subjects carrying this variant have an earlier onset of the condition than those without [average 44.0±14.0 (n = 16) versus 54.4±16.1 (n = 36) years old, p = 0.054]. In both human and mouse inner ear tissues, PCDHGA10 is expressed in ganglia, hair cells and vestibular transitional epithelia. Fluorescent RNA in situ hybridization using mouse inner ear tissues shows that expression increases with age. In summary, our data show that a variant in the PCDHGA10 gene may be involved in causing or aggravating some familial cases of recurrent idiopathic BPPV.Yinfang XuYan ZhangIvan A LopezJacey HilbersAnthony J GriswoldAkira IshiyamaSusan BlantonXue Zhong LiuYunxia Wang LundbergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 5, p e0251386 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yinfang Xu Yan Zhang Ivan A Lopez Jacey Hilbers Anthony J Griswold Akira Ishiyama Susan Blanton Xue Zhong Liu Yunxia Wang Lundberg Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
description	Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in humans, yet the molecular etiology is currently unknown. Evidence suggests that genetic factors may play an important role in some cases of idiopathic BPPV, particularly in familial cases, but the responsible genetic variants have not been identified. In this study, we performed whole exome sequencing [including untranslated regions (UTRs)] of 12 families and Sanger sequencing of additional 30 families with recurrent BPPV in Caucasians from the United States (US) Midwest region, to identify the genetic variants responsible for heightened susceptibility to BPPV. Fifty non-BPPV families were included as controls. In silico and experimental analyses of candidate variants show that an insertion variant rs113784532 (frameshift causing truncation) in the neural cadherin gene PCDHGA10 (protocadherin-gamma A10) is an exceedingly strong candidate (p = 1.80x10-4 vs. sample controls; p = 5.85x10-19 vs. ExAC data; p = 4.9x10-3 vs. NHLBI exome data). The mutant protein forms large aggregates in BPPV samples even at young ages, and affected subjects carrying this variant have an earlier onset of the condition than those without [average 44.0±14.0 (n = 16) versus 54.4±16.1 (n = 36) years old, p = 0.054]. In both human and mouse inner ear tissues, PCDHGA10 is expressed in ganglia, hair cells and vestibular transitional epithelia. Fluorescent RNA in situ hybridization using mouse inner ear tissues shows that expression increases with age. In summary, our data show that a variant in the PCDHGA10 gene may be involved in causing or aggravating some familial cases of recurrent idiopathic BPPV.
format	article
author	Yinfang Xu Yan Zhang Ivan A Lopez Jacey Hilbers Anthony J Griswold Akira Ishiyama Susan Blanton Xue Zhong Liu Yunxia Wang Lundberg
author_facet	Yinfang Xu Yan Zhang Ivan A Lopez Jacey Hilbers Anthony J Griswold Akira Ishiyama Susan Blanton Xue Zhong Liu Yunxia Wang Lundberg
author_sort	Yinfang Xu
title	Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
title_short	Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
title_full	Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
title_fullStr	Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
title_full_unstemmed	Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
title_sort	identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/38c2bbb8d12249e78cb682cf7cdeecd5
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Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.

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