Nature Genetics
22, 196 - 198 (1999)
doi:10.1038/9718
Mutations in the homeodomain of the human SIX3 gene cause holoprosencephalyDeeann E. Wallis1, Erich Roessler1, 3, Ute Hehr4, Luisa Nanni1, Tim Wiltshire2, Antonio Richieri-Costa5, Gabriele Gillessen-Kaesbach6, Elaine H. Zackai1, Johanna Rommens7
& Maximilian Muenke1, 31
The Children's Hospital of Philadelphia, Departments of Pediatrics, Genetics, Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4399, USA. 2
Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4399, USA. 3
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1852, USA. 4
Department of Human Genetics, University of Halle, Germany. 5
Department of Clinical Genetics, University of San Paulo, Bauru, SP, Brazil. 6
Department of Human Genetics, University of Essen, Germany. 7
Program in Genetics and Genomic Biology, The Hospital for Sick Children, Department of Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Correspondence should be addressed to Maximilian Muenke mmuenke@nhgri.nih.govHoloprosencephaly (HPE) is a common, severe malformation of the brain that involves separation of the central nervous system into left and right halves. Mild HPE can consist of signs such as a single central incisor, hypotelorism, microcephaly, or other craniofacial findings that can be present with or without associated brain malformations1,
2,
3. The aetiology of HPE is extremely heterogeneous, with the proposed participation of a minimum of 12 HPE-associated genetic loci as well as the causal involvement of specific teratogens acting at the earliest stages of neurulation4. The HPE2 locus was recently characterized as a 1-Mb interval on human chromosome 2p21 that contained a gene associated with HPE. A minimal critical region was defined by a set of six overlapping deletions and three clustered translocations in HPE patients5. We describe here the isolation and characterization of the human homeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). We show that at least 2 of the HPE-associated translocation breakpoints in 2p21 are less than 200 kb from the 5´ end of SIX3. Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE. We propose that SIX3 is the HPE2 gene, essential for the development of the anterior neural plate and eye in humans.
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