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

Am J Hum Genet. 2012 Feb 10;90(2):247-59. doi: 10.1016/j.ajhg.2011.12.019. Epub 2012 Jan 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anterior Eye Segment / abnormalities
  • Anterior Eye Segment / embryology*
  • Base Sequence
  • Brain / pathology
  • Cerebral Palsy / genetics
  • Cerebral Palsy / metabolism
  • Cornea / abnormalities*
  • Corneal Diseases / genetics
  • Corneal Diseases / metabolism
  • DNA Copy Number Variations / genetics
  • Eye Abnormalities / complications
  • Eye Abnormalities / embryology
  • Eye Abnormalities / genetics*
  • Eye Proteins / biosynthesis
  • Eye Proteins / genetics*
  • Female
  • Genes, X-Linked
  • Genetic Diseases, X-Linked / complications
  • Genetic Diseases, X-Linked / embryology
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • Male
  • Megalencephaly / genetics
  • Megalencephaly / metabolism
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Phenotype
  • Quantitative Trait Loci
  • Retina / abnormalities
  • Retina / embryology
  • Young Adult


  • CHRDL1 protein, human
  • Eye Proteins
  • Nerve Tissue Proteins

Supplementary concepts

  • Neuhauser syndrome