title: Leber's congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p.
abstract: BACKGROUND
  Leber's congenital amaurosis (LCA) represents the earliest and severest form of retinal dystrophy leading to congenital blindness. A total of 20% of children attending blind schools have this disease. LCA has a multigenic basis and is proving central to our understanding of the development of the retina. We describe the clinical and molecular genetic features of four inbred pedigrees from neighbouring remote villages in northern Pakistan, in which some of the affected members have concurrent keratoconus.
  
  
  METHODS
  History-taking and physical and eye examinations were performed in the field. Venipuncture, DNA extraction, studies of linkage to known LCA genes, automated sequencing and polymorphism analyses for haplotype assessments were done.
  
  
  RESULTS
  We examined 12 affected and 15 unaffected family members. By history, there were an additional nine blind people in the four pedigrees. In each pedigree a consanguineous marriage was evident. We found a homozygous nonsense mutation in the AIPL1 gene, which replaces a tryptophan with a stop codon (Trp278X). The phenotype is severe and variable, despite the common molecular genetic etiology in each family. Affected patients had hand motion to no light perception vision and fundus findings ranging from maculopathy to diffuse pigmentary retinopathy. Three affected members had definite keratoconus, and two were suspects based on mild cone formation in the cornea of at least one eye.
  
  
  CONCLUSIONS
  We have identified four Pakistani families with a severe form of LCA that is associated with severe keratoconus in some affected members. The molecular etiology in all four families is a homozygous nonsense mutation, Trp278X, in the photoreceptor-pineal gene AIPL1. To our knowledge, this is one of the first phenotype-genotype correlations of AIPL1-associated LCA.
authors.affiliation: Ottawa Hospital Research Institute, Ont. kdamji@ottahospital.on.ca
authors.forename: K F
authors.initials: KF
authors.lastname: Damji
authors.forename: M M
authors.initials: MM
authors.lastname: Sohocki
authors.forename: R
authors.initials: R
authors.lastname: Khan
authors.forename: S K
authors.initials: SK
authors.lastname: Gupta
authors.forename: M
authors.initials: M
authors.lastname: Rahim
authors.forename: M
authors.initials: M
authors.lastname: Loyer
authors.forename: N
authors.initials: N
authors.lastname: Hussein
authors.forename: N
authors.initials: N
authors.lastname: Karim
authors.forename: S S
authors.initials: SS
authors.lastname: Ladak
authors.forename: A
authors.initials: A
authors.lastname: Jamal
authors.forename: D
authors.initials: D
authors.lastname: Bulman
authors.forename: R K
authors.initials: RK
authors.lastname: Koenekoop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D001766:Blindness / Q000208:ethnology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D018389:Codon, Nonsense; D018388:Codon, Terminator; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005136:Eye Proteins; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007640:Keratoconus / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D029242:Optic Atrophy, Hereditary, Leber / Q000208:ethnology / Q000235:genetics*; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree; D011110:Polymorphism, Genetic; D012174:Retinitis Pigmentosa / Q000208:ethnology / Q000235:genetics*; D014364:Tryptophan
chemical_list: C403625:AIPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018389:Codon, Nonsense; D018388:Codon, Terminator; D005136:Eye Proteins; D014364:Tryptophan