Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies
✍ Scribed by Preeti Bakrania; Sibel A. Ugur Iseri; Alexander W. Wyatt; Dave J. Bunyan; Wayne W.K. Lam; Alison Salt; Jacqueline Ramsay; David O. Robinson; Nicola K. Ragge
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 175 KB
- Volume
- 152A
- Category
- Article
- ISSN
- 1552-4825
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✦ Synopsis
The hedgehog (Hh) signaling cascade is crucial for the correct development and patterning of various vertebrate tissues and organs, including the brain and spinal cord, eye, craniofacial structures, and the limbs [reviewed in Simpson et al., 2009]. The morphogen Sonic hedgehog (Shh) is a well-established ligand of the Hh pathway, where it is first synthesized as a non-functional precursor peptide, followed by an autocatalytic cleavage into N and C terminal domains (Shh-N and Shh-C). The lipidified Shh-N is the functionally active ligand, while Shh-C is regarded as the catalytic domain for the autocatalytic process [Ma et al., 2008].
In humans, SHH has been implicated as the major gene in holoprosencephaly (HPE, OMIM 236100), which results from abnormal or incomplete separation of the prosencephalon into two hemispheres. At the severe end of the spectrum, the forebrain defect can be accompanied by marked facial dysmorphism and severe ocular anomalies, such as anophthalmia (congenital absence of the eye) or microphthalmia (congenitally small eye), cyclopia with a proboscis-like nasal structure as well as cleft lip/palate. At the milder end, HPE may occasionally be accompanied by iris and chorioretinal coloboma or cataract in addition to hypotelorism and tooth anomalies [reviewed in Dubourg et al., 2007]. Interestingly, two reports suggest that chromosomal abnormalities [Ginocchio et al., 2008] or mutations [Schimmenti et al., 2003] involving SHH may result in isolated ocular anomalies such as microphthalmia and coloboma without the typical cerebral features of HPE. Further evidence for SHH as a potentially important signaling molecule for human eye development was our demonstration of SHH expression in the early developing human embryonic eye, co-spatially and cotemporally with other developmental eye genes, such as BMP4 [Bakrania et al., 2008].
To elucidate the range of ocular phenotypes that may be caused by mutations or deletions, we screened a cohort of 236 individuals with developmental eye anomalies, principally microphthalmia, anophthalmia and coloboma recruited as part of a national study