ArticleHuman molecular genetics2008
Mutations in the human SIX3 gene in holoprosencephaly are loss of function.
Article in Human molecular genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 57 citations in OpenAlex.
- SIX3 as a Regulator of Development and Disease.Journal of developmental biology · 2026Review
- Efficacy of tolvaptan in an infant with syndrome of inappropriate antidiuretic hormone secretion associated with holoprosencephaly: A case report.World journal of clinical cases · 2023Article
- MicroRNA and MicroRNA-Target Variants Associated with Autism Spectrum Disorder and Related Disorders.Genes · 2022Article
- Study on the Correlation Between Iris Characteristics and Schizophrenia.Neuropsychiatric disease and treatment · 2022Article
- High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.American journal of human genetics · 2021Article
- NewMolecular syndromology · 2021Article
- Developmental Genes and Malformations in the Hypothalamus.Frontiers in neuroanatomy · 2020Review
- SIX3 and SIX6 interact with GEMININ via C-terminal regions.Biochemistry and biophysics reports · 2019Article
- A novel mutation in the glucocorticoid receptor gene as a cause of severe glucocorticoid resistance complicated by hypertensive encephalopathy.Journal of hypertension · 2019Article
- SSS-test: a novel test for detecting positive selection on RNA secondary structure.BMC bioinformatics · 2019Article
- SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly.Congenital anomalies · 2018Article
- Rare novel variants in the ZIC3 gene cause X-linked heterotaxy.European journal of human genetics : EJHG · 2016Article
- A trans-Regulatory Code for the Forebrain Expression of Six3.2 in the Medaka Fish.The Journal of biological chemistry · 2015Article
- Ethanol alters gene expression and cell organization during optic vesicle evagination.Neuroscience · 2013Article
- Six3 cooperates with Hedgehog signaling to specify ventral telencephalon by promoting early expression of Foxg1a and repressing Wnt signaling.Development (Cambridge, England) · 2012Article
- Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions.Molecular genetics and metabolism · 2012Article
- The visual system of zebrafish and its use to model human ocular diseases.Developmental neurobiology · 2012Review
- Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH.Human genetics · 2012Article
- Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.Human mutation · 2011Article
- A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum.American journal of medical genetics. Part A · 2011Article
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Authors and funding
10 authors at 1 institution in 1 country.
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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.
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