Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly

Deeann E. Wallis, Erich Roessler, Ute Hehr, Luisa Nanni, Tim Wiltshire, Antonio Richieri-Costa, Gabriele Gillessen-Kaesbach, Elaine H. Zackai, Johanna Rommens, Maximilian Muenke*

*Corresponding author for this work
322 Citations (Scopus)


Holoprosencephaly (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 malformations. 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 neurulation. 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 patients. 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.

Original languageEnglish
JournalNature Genetics
Issue number2
Pages (from-to)196-198
Number of pages3
Publication statusPublished - 06.1999

Research Areas and Centers

  • Research Area: Medical Genetics


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