Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia

•Two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin were reported.•A novel nonsense HOXA2 mutation was identified, and a mutational hotspot is implicated.•These mutations could impair the activation of HMX1 by interacting with a long-range enhancer. HOX genes are impor...

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Veröffentlicht in:Gene 2020-10, Vol.757, p.144945-144945, Article 144945
Hauptverfasser: Si, Nuo, Meng, Xiaolu, Lu, Xiaosheng, Zhao, Xuelian, Li, Chuan, Yang, Meirong, Zhang, Ye, Wang, Changchen, Guo, Peipei, Zhang, Xue, Pan, Bo, Jiang, Haiyue
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container_title Gene
container_volume 757
creator Si, Nuo
Meng, Xiaolu
Lu, Xiaosheng
Zhao, Xuelian
Li, Chuan
Yang, Meirong
Zhang, Ye
Wang, Changchen
Guo, Peipei
Zhang, Xue
Pan, Bo
Jiang, Haiyue
description •Two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin were reported.•A novel nonsense HOXA2 mutation was identified, and a mutational hotspot is implicated.•These mutations could impair the activation of HMX1 by interacting with a long-range enhancer. HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A > T, p.Lys213*) is newly reported, while the other one (c.703C > T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer.
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HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A &gt; T, p.Lys213*) is newly reported, while the other one (c.703C &gt; T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer.</description><identifier>ISSN: 0378-1119</identifier><identifier>EISSN: 1879-0038</identifier><identifier>DOI: 10.1016/j.gene.2020.144945</identifier><language>eng</language><publisher>Elsevier B.V</publisher><subject>Autosomal dominant inheritance ; HMX1 ; HOXA2 ; Microtia</subject><ispartof>Gene, 2020-10, Vol.757, p.144945-144945, Article 144945</ispartof><rights>2020 Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c333t-10729c29afdf5f681a16511c6e470bf19bd6c80743396156c0ad36231bf196633</citedby><cites>FETCH-LOGICAL-c333t-10729c29afdf5f681a16511c6e470bf19bd6c80743396156c0ad36231bf196633</cites><orcidid>0000-0001-9215-9024 ; 0000-0002-1985-3420</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.gene.2020.144945$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids></links><search><creatorcontrib>Si, Nuo</creatorcontrib><creatorcontrib>Meng, Xiaolu</creatorcontrib><creatorcontrib>Lu, Xiaosheng</creatorcontrib><creatorcontrib>Zhao, Xuelian</creatorcontrib><creatorcontrib>Li, Chuan</creatorcontrib><creatorcontrib>Yang, Meirong</creatorcontrib><creatorcontrib>Zhang, Ye</creatorcontrib><creatorcontrib>Wang, Changchen</creatorcontrib><creatorcontrib>Guo, Peipei</creatorcontrib><creatorcontrib>Zhang, Xue</creatorcontrib><creatorcontrib>Pan, Bo</creatorcontrib><creatorcontrib>Jiang, Haiyue</creatorcontrib><title>Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia</title><title>Gene</title><description>•Two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin were reported.•A novel nonsense HOXA2 mutation was identified, and a mutational hotspot is implicated.•These mutations could impair the activation of HMX1 by interacting with a long-range enhancer. HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A &gt; T, p.Lys213*) is newly reported, while the other one (c.703C &gt; T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer.</description><subject>Autosomal dominant inheritance</subject><subject>HMX1</subject><subject>HOXA2</subject><subject>Microtia</subject><issn>0378-1119</issn><issn>1879-0038</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kE9LAzEQxYMoWKtfwFOOXrbmz252F7yUorZQ6EXBW0izk3bKblI3qeK3d9t6di4Db94bZn6E3HM24Yyrx91kAx4mgolByPM6Ly7IiFdlnTEmq0syYrKsMs55fU1uYtyxoYpCjMhm0YBP6NCahMHT4GgbYsyCy9zB25M2X31MBe0O6WSJFD2dbdFDBOpMhy1CpN-YtrQJHXrjE11jaxL0pqUd2j4kNLfkypk2wt1fH5P3l-e32Txbrl4Xs-kys1LKlHFWitqK2rjGFU5V3HBVcG4V5CVbO16vG2UrVuZS1ooXyjLTSCUkP86UknJMHs579334PEBMusNooW2Nh3CIWuRCMlUWVTlYxdk6XBhjD07ve-xM_6M500eqeqePVPWRqj5THUJP5xAMT3wh9DpaBG-hwR5s0k3A_-K_raiAaw</recordid><startdate>20201005</startdate><enddate>20201005</enddate><creator>Si, Nuo</creator><creator>Meng, Xiaolu</creator><creator>Lu, Xiaosheng</creator><creator>Zhao, Xuelian</creator><creator>Li, Chuan</creator><creator>Yang, Meirong</creator><creator>Zhang, Ye</creator><creator>Wang, Changchen</creator><creator>Guo, Peipei</creator><creator>Zhang, Xue</creator><creator>Pan, Bo</creator><creator>Jiang, Haiyue</creator><general>Elsevier B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9215-9024</orcidid><orcidid>https://orcid.org/0000-0002-1985-3420</orcidid></search><sort><creationdate>20201005</creationdate><title>Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia</title><author>Si, Nuo ; Meng, Xiaolu ; Lu, Xiaosheng ; Zhao, Xuelian ; Li, Chuan ; Yang, Meirong ; Zhang, Ye ; Wang, Changchen ; Guo, Peipei ; Zhang, Xue ; Pan, Bo ; Jiang, Haiyue</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c333t-10729c29afdf5f681a16511c6e470bf19bd6c80743396156c0ad36231bf196633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Autosomal dominant inheritance</topic><topic>HMX1</topic><topic>HOXA2</topic><topic>Microtia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Si, Nuo</creatorcontrib><creatorcontrib>Meng, Xiaolu</creatorcontrib><creatorcontrib>Lu, Xiaosheng</creatorcontrib><creatorcontrib>Zhao, Xuelian</creatorcontrib><creatorcontrib>Li, Chuan</creatorcontrib><creatorcontrib>Yang, Meirong</creatorcontrib><creatorcontrib>Zhang, Ye</creatorcontrib><creatorcontrib>Wang, Changchen</creatorcontrib><creatorcontrib>Guo, Peipei</creatorcontrib><creatorcontrib>Zhang, Xue</creatorcontrib><creatorcontrib>Pan, Bo</creatorcontrib><creatorcontrib>Jiang, Haiyue</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Si, Nuo</au><au>Meng, Xiaolu</au><au>Lu, Xiaosheng</au><au>Zhao, Xuelian</au><au>Li, Chuan</au><au>Yang, Meirong</au><au>Zhang, Ye</au><au>Wang, Changchen</au><au>Guo, Peipei</au><au>Zhang, Xue</au><au>Pan, Bo</au><au>Jiang, Haiyue</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia</atitle><jtitle>Gene</jtitle><date>2020-10-05</date><risdate>2020</risdate><volume>757</volume><spage>144945</spage><epage>144945</epage><pages>144945-144945</pages><artnum>144945</artnum><issn>0378-1119</issn><eissn>1879-0038</eissn><abstract>•Two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin were reported.•A novel nonsense HOXA2 mutation was identified, and a mutational hotspot is implicated.•These mutations could impair the activation of HMX1 by interacting with a long-range enhancer. HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A &gt; T, p.Lys213*) is newly reported, while the other one (c.703C &gt; T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer.</abstract><pub>Elsevier B.V</pub><doi>10.1016/j.gene.2020.144945</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-9215-9024</orcidid><orcidid>https://orcid.org/0000-0002-1985-3420</orcidid></addata></record>
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subjects Autosomal dominant inheritance
HMX1
HOXA2
Microtia
title Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia
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