A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome

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dc.contributor.authorPohl, Esther
dc.contributor.authorAykut, Ayca
dc.contributor.authorBeleggia, Filippo
dc.contributor.authorKaraca, Emin
dc.contributor.authorDurmaz, Burak
dc.contributor.authorKeupp, Katharina
dc.contributor.authorArslan, Esra
dc.contributor.authorOnay, Melis Palamar
dc.contributor.authorYigit, Goekhan
dc.contributor.authorÖzkınay, Ferda
dc.contributor.authorWollnik, Bernd
dc.date.accessioned2019-10-27T22:07:28Z
dc.date.available2019-10-27T22:07:28Z
dc.date.issued2013
dc.departmentEge Üniversitesien_US
dc.description.abstractOtofaciocervical syndrome (OFCS) is an autosomal recessively inherited disorder characterized by facial dysmorphism, external ear anomalies with preauricular pits and hearing impairment, branchial cysts or fistulas, anomalies of the vertebrae and the shoulder girdle, and mild intellectual disability. In a large consanguineous family with OFCS from Turkey, we performed whole-exome sequencing (WES) of a single pooled DNA sample of four affected individuals. Filtering for variants with a percentage of alternate reads a parts per thousand yen90 % and a coverage of at least five reads identified only a single novel homozygous variant, c.497G > T, located in PAX1 that co-segregated with the disease in the family. PAX1 encodes a transcription factor with a critical role in pattern formation during embryogenesis in vertebrates. The mutation is predicted to substitute the glycine at position 166 to valine (p.G166V) within the highly conserved paired-box domain of the PAX1 protein. We performed a dual luciferase reporter assay to examine the transactivation of a regulatory sequence in the Nkx3-2 promoter region, which is a direct target of mouse Pax1 transcriptional regulation. We observed a significantly reduced transactivation in HEK293T cells overexpressing Pax1(G157V) in comparison to Pax1(WT) expressing cells, indicating a reduced DNA-binding affinity of the mutant protein. Taken together, our results show that the strategy of pooling DNA is a powerful, cost-effective application for WES in consanguineous families and establish PAX1 as a new disease-causing gene for OFCS and as part of the EYA-DACH-SIX-PAX network, important in early embryogenesis.en_US
dc.description.sponsorshipGerman Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1211A]en_US
dc.description.sponsorshipWe are grateful to all family members who participated in this study, to Esther Milz for excellent technical assistance, to Andrea Pannes for her technical advice in slow-down PCR, to Simon von Ameln for cochlea preparation, and to Karin Boss for critically reading the manuscript. This work was supported by the German Federal Ministry of Education and Research (BMBF) by grant number 01GM1211A (E-RARE network CRANIRARE-2) to B. W.en_US
dc.identifier.doi10.1007/s00439-013-1337-9en_US
dc.identifier.endpage1320en_US
dc.identifier.issn0340-6717
dc.identifier.issn1432-1203
dc.identifier.issue11en_US
dc.identifier.pmid23851939en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1311en_US
dc.identifier.urihttps://doi.org/10.1007/s00439-013-1337-9
dc.identifier.urihttps://hdl.handle.net/11454/49018
dc.identifier.volume132en_US
dc.identifier.wosWOS:000325706500011en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.relation.ispartofHuman Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.titleA hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndromeen_US
dc.typeArticleen_US

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