X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development

Tom R Webb ,Tin Aung,Mahinda Yogarajah,Michel Michaelides,Hala Hassan,Seyhan Yazar,Jessica C Gardner ,Sanjay M Sisodiya ,Michael E Cheetham ,Anthony T Moore ,Anthony G Robson ,Jonathan B Ruddle ,Elias I Traboulsi ,David A Mackey ,Craig E Pennell ,Jane C Sowden ,Daniel Kelberman ,Wei Chern Ang ,Stephen Tuft ,Chiea‐Chuen Khor ,Mar Matarı́n ,Graham E Holder ,Alison J Hardcastle

doi:10.1016/j.ajhg.2011.12.019

Abstract

X-linked megalocornea (MGC1) is an ocular anterior segment disorder characterized by an increased cornea diameter and deep anterior chamber evident at birth and later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. We identified copy-number variation, frameshift, missense, splice-site and nonsense mutations in the Chordin-like 1 gene (CHRDL1) on Xq23 as the cause of the condition in seven MGC1 families. CHRDL1 encodes ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections. Electrophysiological evaluation revealed mild generalized cone system dysfunction and, in one patient, an interhemispheric asymmetry in visual evoked potentials. We show 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 is differentially expressed in the human fetal brain, and there is high expression in cerebellum and neocortex. We show that MGC1 patients have a superior cognitive ability despite a striking focal loss of myelination of white matter. Our findings reveal an unexpected requirement for ventroptin during anterior segment development and the consequences of a lack of function in the retina and brain.

Highlights

Anterior segment dysgenesis describes a range of phenotypes caused by failure of normal development of the anterior segment of the eye.[1]
Standard evaluation consisted of detailed ophthalmic examination and the additional measurement of the axial length of the eye and imaging of the anterior segment of the eye performed with ocular coherence tomography (OCT; Visante, Carl Zeiss Meditec), b-scan ultrasonography, and optical interferometry (IOLMaster, Carl Zeiss Meditec)
Regulation of bone morphogenic proteins (BMPs) signaling is important for both patterning and control of organ size during embryogenesis and is tightly controlled by extracellular and intracellular mechanisms

Summary

Introduction

Anterior segment dysgenesis describes a range of phenotypes caused by failure of normal development of the anterior segment of the eye.[1] These anomalies are often associated with an increased risk of glaucoma, corneal opacity, and loss of vision. X-linked megalocornea (MGC1 [MIM 309300]), a bilateral and developmental anomaly of the anterior segment of the eye, is characterized by a thin cornea of increased diameter (generally >12.5 mm at birth) and a very deep anterior chamber but no increase in intraocular pressure.[2] In older patients, MGC1 is associated with distinctive secondary changes of mosaic corneal degeneration (shagreen) and corneal arcus juvenilis. Pathological changes include mild iris atrophy with pigment dispersion, lens dislocation, and cataracts.[2,3] Corneal endothelial cells have a normal morphology and cell density, which suggests that corneal endothelial cell hyperplasia occurs concurrently with excessive corneal growth.[4]

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Results

Conclusion