title: A missense mutation in the nuclear localization signal sequence of CERKL (p.R106S) causes autosomal recessive retinal degeneration.
abstract: OBJECTIVE
  To investigate the genetic basis of autosomal recessive retinal degeneration in a large consanguineous family from Pakistan.
  
  
  METHODS
  Ophthalmic examinations were conducted on family members to establish their diagnosis. Genomic DNA extracted from peripheral blood was used for homozygosity mapping to discover the chromosomal region that harbors the defective gene. Direct sequence analysis and restriction enzyme digestion were used to identify and confirm the defect in the gene.
  
  
  RESULTS
  There were three affected siblings in the family, each with limited peripheral vision and impaired visual acuity. We established linkage to a region on chromosome 2 that encompasses the RP26 locus. Upon sequencing the ceramide kinase-like (CERKL) gene, which is mutated in the original RP26 family, we identified a C>A transversion in exon 2 (c.316C>A) that substitutes an arginine residue with a serine (p.R106S) in the conserved nuclear localization signal sequence (KLKRR) of the protein. This mutation segregated with retinal degeneration in the Pakistani family and was not observed in the DNA of 174 ethnically matched unaffected controls.
  
  
  CONCLUSIONS
  This is the third reported mutation in CERKL causing retinal degeneration but is the first report to show that a single amino acid change in CERKL, rather than a null mutation, can cause retinal disease. Although the function of CERKL is still unknown, the mutation described herein confirms that the nuclear localization signal sequence is important in the physiologic function of the protein.
authors.affiliation: Section of Ophthalmology and Neuroscience, 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: Vedam Lakshmi
authors.initials: VL
authors.lastname: Ramprasad
authors.forename: Nagasamy
authors.initials: N
authors.lastname: Soumittra
authors.forename: Moin D
authors.initials: MD
authors.lastname: Mohamed
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rashid
authors.forename: Michael
authors.initials: M
authors.lastname: Danciger
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Kumaramanickavel
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D019913:Nuclear Localization Signals / Q000235:genetics*; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics*
chemical_list: D019913:Nuclear Localization Signals; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase