Wieczorek, Dagmar and Newman, William G. and Wieland, Thomas and Berulava, Tea and Kaffe, Maria and Falkenstein, Daniela and Beetz, Christian and Graf, Elisabeth and Schwarzmayr, Thomas and Douzgou, Sofia and Clayton-Smith, Jill and Daly, Sarah B. and Williams, Simon G. and Bhaskar, Sanjeev S. and Urquhart, Jill E. and Anderson, Beverley and O'Sullivan, James and Boute, Odile and Gundlach, Jasmin and Czeschik, Johanna Christina and van Essen, Anthonie J. and Hazan, Filiz and Park, Sarah and Hing, Anne and Kuechler, Alma and Lohmann, Dietmar R. and Ludwig, Kerstin U. and Mangold, Elisabeth and Steenpass, Laura and Zeschnigk, Michael and Lemke, Johannes R. and Lourenco, Charles Marques and Hehr, Ute and Prott, Eva-Christina and Waldenberger, Melanie and Boehmer, Anne C. and Horsthemke, Bernhard and O'Keefe, Raymond T. and Meitinger, Thomas and Bum, John and Luedecke, Hermann-Josef and Strom, Tim M. (2014) Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations in TXNL4A Causes Burn-McKeown Syndrome. AMERICAN JOURNAL OF HUMAN GENETICS, 95 (6). pp. 698-707. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The US spliceosomal complex of eight highly conserved proteins is critical for premRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dibl) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NONSYNDROMIC CLEFT-LIP; OTO-FACIAL DYSPLASIA; CHOANAL ATRESIA; PALATE; HAPLOINSUFFICIENCY; INHERITANCE; COMPLEX; PROTEIN; SNRNP; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Aug 2019 12:06 |
| Last Modified: | 06 Aug 2019 12:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9077 |
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