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Jessica C. Gardner, Tom R. Webb, Mar Matarin, Elias I. Traboulsi, Jane C. Sowden, Michel Michaelides, Sanjay M. Sisodiya, David A. Mackey, Stephen J. Tuft, Alison J. Hardcastle; CHRDL1 Mutations Cause X-linked Megalocornea and Reveal an Unexpected Role for the Encoded Protein Ventroptin in Anterior Segment Development. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2254.
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X-linked Megalocornea (MGC1) is an anterior segment disorder characterised by an increased corneal diameter and deep anterior chamber evident at birth, mild iris atrophy with pigment dispersion and lens dislocation with later onset of mosaic corneal degeneration, arcus juvenilis and presenile cataracts. MGC1 was previously mapped to a 24 Mb interval on Xq. We characterised new MGC1 families to facilitate disease gene identification.
Clinical evaluation included imaging of the retina and anterior segment, electrophysiological assessment and measurement of axial length, corneal diameter and central corneal thickness. Genetic analysis included dense X-chromosome array comparative genomic hybridisation (CGH), amplification and sequencing of the Chordin-like 1 (CHRDL1) gene and deletion-breakpoint analysis. In situ hybridisation was performed in the developing human eye. Gene expression data for CHRDL1 in human fetal brain tissue was analysed, and functional MRI and cognitive tests performed on 2 subjects.
Using dense X-chromosome array CGH, we identified a 250 Kb deletion on Xq23 in an affected male. The deletion, which encompassed the 3’ end of CHRDL1, segregated with disease. Mutation screening of CHRDL1 in 6 other MGC1 families identified frameshift, nonsense, missense and splice site mutations and a second deletion encompassing the entire CHRDL1 gene. CHRDL1 encodes Ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections. Electrophysiological evaluation showed mild generalised cone system dysfunction. In situ hybridisation established that CHRDL1 is expressed in the developing human cornea and anterior segment in addition to the retina. We explored the impact of loss of Ventroptin function on brain function and morphology in vivo. CHRDL1 was differentially expressed in human fetal brain with high expression in cerebellum and neocortex. MGC1 patients have superior cognitive ability despite striking focal loss of myelination of white matter.
All 7 MGC1 families were found to have a mutation in the CHRDL1 gene. Our findings reveal an unexpected requirement for Ventroptin during anterior segment development, and the consequences of lack of function in the retina and brain.
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