title: Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis.
abstract: OBJECTIVE
  Leber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a "ciliopathy."
  
  
  METHODS
  Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation.
  
  
  RESULTS
  A c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation.
  
  
  CONCLUSIONS
  We report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease.
authors.affiliation: Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya Chennai, India.
authors.forename: Vedam Lakshmi
authors.initials: VL
authors.lastname: Ramprasad
authors.forename: Nagasamy
authors.initials: N
authors.lastname: Soumittra
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.forename: Parveen
authors.initials: P
authors.lastname: Sen
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.forename: Grange A
authors.initials: GA
authors.lastname: Williams
authors.forename: Tharigopala
authors.initials: T
authors.lastname: Arokiasamy
authors.forename: Praveena
authors.initials: P
authors.lastname: Lakshmipathy
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Kumaramanickavel
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D001766:Blindness / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005654:Fundus Oculi; D006801:Humans; D007223:Infant; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D005136:Eye Proteins; C522405:LCA5 protein, human; D008869:Microtubule-Associated Proteins; D022821:RNA Splice Sites