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- Title
Mutations in the human SIX3 gene in holoprosencephaly are loss of function.
- Authors
Domené, Sabina; Roessler, Erich; El-Jaick, Kenia B; Snir, Mirit; Brown, Jamie L; Vélez, Jorge I; Bale, Sherri; Lacbawan, Felicitas; Muenke, Maximilian; Feldman, Benjamin
- Abstract
Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain; however, the genetics of this heterogeneous and etiologically complex malformation is incompletely understood. Heterozygous mutations in SIX3, a transcription factor gene expressed in the anterior forebrain and eyes during early vertebrate development, have been frequently detected in human HPE cases. However, only a few mutations have been investigated with limited functional studies that would confirm a role in HPE pathogenesis. Here, we report the development of a set of robust and sensitive assays of human SIX3 function in zebrafish and apply these to the analysis of a total of 46 distinct mutations (19 previously published and 27 novel) located throughout the entire SIX3 gene. We can now confirm that 89% of these putative deleterious mutations are significant loss-of-function alleles. Since disease-associated single point mutations in the Groucho-binding eh1-like motif decreases the function in all assays, we can also confirm that this interaction is essential for human SIX3 co-repressor activity; we infer, in turn, that this function is important in HPE causation. We also unexpectedly detected truncated versions with partial function, yet missing a SIX3-encoded homeodomain. Our data indicate that SIX3 is a frequent target in the pathogenesis of HPE and demonstrate how this can inform the genetic counseling of families.
- Publication
Human molecular genetics, 2008, Vol 17, Issue 24, p3919
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/ddn294