Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6

Sparrow, Duncan B., McInerney-Leo, Aideen, Gucev, Zoran S., Gardiner, Brooke, Marshall, Mhairi, Leo, Paul J., Chapman, Deborah L., Tasic, Velibor, Shishko, Abduhadi, Brown, Matthew A., Duncan, Emma L., & Dunwoodie, Sally L. (2013) Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Human Molecular Genetics, 22(8), pp. 1625-1631.

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In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic basis of several forms of autosomal recessive SCD cases has been solved with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here, we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.

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ID Code: 89276
Item Type: Journal Article
Refereed: Yes
Keywords: brain protein, DLL3 protein, HES7 protein, LFNG protein, MESP2 protein, TBX6 protein, unclassified drug, article, autosomal dominant disorder, autosomal dominant spondylocostal dysostosis, autosomal recessive disorder, controlled study, disease severity, exome, exome capture, gene mutation, gene sequence, genetic association, genetic identification, haploinsufficiency, human, incidence, Jarcho Levin syndrome, loss of function mutation, next generation sequencing, precursor, priority journal, stoploss mutation, transcription initiation, Abnormalities, Multiple, Animals, Body Patterning, Disease Models, Animal, Genes, Dominant, Heart Defects, Congenital, Hernia, Diaphragmatic, Humans, Mice, Mutation, Pedigree, Sequence Analysis, DNA, Somites, T-Box Domain Proteins
DOI: 10.1093/hmg/ddt012
ISSN: 0964-6906
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 The Authors
Deposited On: 19 Oct 2015 22:43
Last Modified: 20 Mar 2016 23:26

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