title: Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa.
abstract: OBJECTIVE
  To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease.
  
  
  METHODS
  Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing.
  
  
  RESULTS
  The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Müller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele).
  
  
  CONCLUSIONS
  These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.
authors.affiliation: Sections of Ophthalmology, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, United Kingdom. medma@leeds.ac.uk
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hocking
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.forename: Sorcha
authors.initials: S
authors.lastname: Finnegan
authors.forename: Mike
authors.initials: M
authors.lastname: Shires
authors.forename: James A
authors.initials: JA
authors.lastname: Poulter
authors.forename: Katrina
authors.initials: K
authors.lastname: Prescott
authors.forename: Adam
authors.initials: A
authors.lastname: Booth
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Raashid
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Carmel
authors.initials: C
authors.lastname: Toomes
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Lester
authors.forename: David W
authors.initials: DW
authors.lastname: Burt
authors.forename: William J
authors.initials: WJ
authors.lastname: Curry
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D002645:Chickens; D004195:Disease Models, Animal; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005838:Genotype; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D018613:Microscopy, Confocal; D009154:Mutation; D012162:Retinal Degeneration / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; C111442:MPDZ protein, human; D008565:Membrane Proteins