Human Molecular Genetics Advance Access originally published online on September 12, 2008
Human Molecular Genetics 2008 17(24):3919-3928; doi:10.1093/hmg/ddn294
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published by Oxford University Press 2008
Mutations in the human SIX3 gene in holoprosencephaly are loss of function
1 Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA 2 GeneDx, Gaithersburg, MD 20877, USA
* To whom correspondence should be addressed at: Medical Genetics Branch National Human Genome Research Institute National Institutes of Health 35 Convent Drive, MSC 3717 Building 35, Room 1B-205, Bethesda, MD 20892-3717, USA. Tel: +1 3014026690; Fax: +1 301-496-7184; Email: bfeldman{at}mail.nih.gov
Received April 29, 2008; Accepted September 9, 2008
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.
Present address: INGEBI, Buenos Aires C1428ADN, Argentina.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F Lacbawan, B D Solomon, E Roessler, K El-Jaick, S Domene, J I Velez, N Zhou, D Hadley, J Z Balog, R Long, et al. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function J. Med. Genet., June 1, 2009; 46(6): 389 - 398. [Abstract] [Full Text] [PDF]
|
|