PUBLICATION
Mutations in the human SIX3 gene in holoprosencephaly are loss-of-function
- Authors
- Domené, S., Roessler, E., El-Jaick, K.B., Snir, M., Brown, J.L., Vélez, J.I., Bale, S., Lacbawan, F., Muenke, M., and Feldman, B.
- ID
- ZDB-PUB-080922-4
- Date
- 2008
- Source
- Human molecular genetics 17(24): 3919-3928 (Journal)
- Registered Authors
- Feldman, Benjamin
- Keywords
- none
- MeSH Terms
-
- Alleles
- Amino Acid Motifs/genetics
- Amino Acid Sequence
- Amino Acid Substitution/genetics
- Animals
- DNA Mutational Analysis
- Eye Proteins/genetics*
- Eye Proteins/physiology
- Holoprosencephaly/etiology
- Holoprosencephaly/genetics*
- Holoprosencephaly/metabolism*
- Homeodomain Proteins/genetics*
- Homeodomain Proteins/physiology
- Humans
- Molecular Sequence Data
- Nerve Tissue Proteins/genetics*
- Nerve Tissue Proteins/physiology
- Point Mutation/genetics*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 18791198 Full text @ Hum. Mol. Genet.
Citation
Domené, S., Roessler, E., El-Jaick, K.B., Snir, M., Brown, J.L., Vélez, J.I., Bale, S., Lacbawan, F., Muenke, M., and Feldman, B. (2008) Mutations in the human SIX3 gene in holoprosencephaly are loss-of-function. Human molecular genetics. 17(24):3919-3928.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping