title: Absence of NR2E1 mutations in patients with aniridia.
abstract: OBJECTIVE
  Nuclear receptor 2E1 (NR2E1) is a transcription factor with many roles during eye development and thus may be responsible for the occurrence of certain congenital eye disorders in humans. To test this hypothesis, we screened NR2E1 for candidate mutations in patients with aniridia and other congenital ocular malformations (anterior segment dysgenesis, congenital optic nerve malformation, and microphthalmia).
  
  
  METHODS
  The NR2E1 coding region, 5' and 3' untranslated regions (UTRs), exon flanking regions including consensus splice sites, and six evolutionarily conserved non-coding candidate regulatory regions were analyzed by sequencing 58 probands with aniridia of whom 42 were negative for PAX6 mutations. Nineteen probands with anterior segment dysgenesis, one proband with optic nerve malformation, and two probands with microphthalmia were also sequenced. The control population comprised 376 healthy individuals. All sequences were analyzed against the GenBank sequence AL078596.8 for NR2E1. In addition, the coding region and flanking intronic sequences of FOXE3, FOXC1, PITX2, CYP1B1, PAX6, and B3GALTL were sequenced in one patient and his relatives.
  
  
  RESULTS
  Sequencing analysis showed 17 NR2E1 variants including two novel rare non-coding variants (g.-1507G>A, g.14258C>T), and one novel rare coding variant (p.Arg274Gly). The latter was present in a male diagnosed with Peters' anomaly who subsequently was found to have a known causative mutation for Peters' plus syndrome in B3GALTL (c.660+1G>A). In addition, the NR2E1 novel rare variant Arg274Gly was present in the unaffected mother of the patient but absent in 746 control chromosomes.
  
  
  CONCLUSIONS
  We eliminated a major role for NR2E1 regulatory and coding mutations in aniridia and found a novel rare coding variant in NR2E1. In addition, we found no coding region variation in the control population for NR2E1, which further supports its previously reported high level of conservation and low genetic diversity. Future NR2E1 studies in ocular disease groups such as those involving retinal and optic nerve abnormalities should be undertaken to determine whether NR2E1 plays a role in these conditions.
authors.affiliation: Centre for Molecular Medicine and Therapeutics at the Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ximena
authors.initials: X
authors.lastname: Corso-Díaz
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Borrie
authors.forename: Russell
authors.initials: R
authors.lastname: Bonaguro
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Schuetz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.forename: Hanne
authors.initials: H
authors.lastname: Jensen
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
authors.forename: Ian M
authors.initials: IM
authors.lastname: Macdonald
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walter
authors.forename: Karen
authors.initials: K
authors.lastname: Grønskov
authors.forename: Angela
authors.initials: A
authors.lastname: Brooks-Wilson
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Simpson
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000328:Adult; D015783:Aniridia / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008850:Microphthalmos / Q000235:genetics; D009154:Mutation; D016366:Open Reading Frames; D009900:Optic Nerve / Q000002:abnormalities; D057093:Orphan Nuclear Receptors; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D005136:Eye Proteins; C088601:NR2E1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear