Universität zu Köln

Pohl, Esther, Aykut, Ayca, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Karaca, Emin, Durmaz, Burak, Keupp, Katharina, Arslan, Esra, Onay, Melis Palamar, Yigit, Goekhan, Ozkinay, Ferda and Wollnik, Bernd (2013). A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome. Hum. Genet., 132 (11). S. 1311 - 1321. NEW YORK: SPRINGER. ISSN 1432-1203

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Abstract

Otofaciocervical 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pohl, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Aykut, Ayca UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Karaca, Emin UNSPECIFIED UNSPECIFIED UNSPECIFIED Durmaz, Burak UNSPECIFIED UNSPECIFIED UNSPECIFIED Keupp, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Arslan, Esra UNSPECIFIED UNSPECIFIED UNSPECIFIED Onay, Melis Palamar UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozkinay, Ferda UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-473496
DOI:	10.1007/s00439-013-1337-9
Journal or Publication Title:	Hum. Genet.
Volume:	132
Number:	11
Page Range:	S. 1311 - 1321
Date:	2013
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BRANCHIOOTORENAL BOR SYNDROME; GENES; DROSOPHILA; REGION; DOMAIN; CONSERVATION; DISRUPTION; EXPRESSION; PATIENT; MEMBER Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47349