title: Substitution at IL1RN and deletion at SLC4A11 segregating with phenotype in familial keratoconus.
abstract: OBJECTIVE
  Keratoconus (KTCN) is a thinning and anterior protrusion of the cornea that results in altered refractive powers and loss of visual acuity. Despite numerous studies, the reasons for development and progression of KTCN remain unknown. Genetic studies have led to identification of several loci linked with KTCN, including a locus in one multigenerational Ecuadorian family. The purpose of this study was to identify sequence variants in candidate genes segregating with the KTCN phenotype in another Ecuadorian family.
  
  
  METHODS
  Nonparametric linkage analysis was performed in Ecuadorian family KTCN-019. Candidate genes IL1A, IL1B, IL1RN, and SLC4A11 were selected and examined in this family by direct sequencing of all exons, promoters, and intron-exon junctions.
  
  
  RESULTS
  Two novel suggestive loci were identified in 2q13-q14.3 and 20p13-p12.2. Screening of the candidate genes revealed 66 sequence variants, including five novel variants, in both coding and noncoding regions. The substitution c.214+242C > T in the IL1RN gene was observed in all affected individuals and three apparently unaffected family members. The novel deletion of 54 nucleotides in position c.2558+149_2558+203 in SLC4A11 was observed in all patients but one, as well as two healthy individuals and one person with an unknown phenotype.
  
  
  CONCLUSIONS
  The analyses of selected genes have led to identification of numerous sequence variants in the examined Ecuadorian family. Both substitution c.214+242C > T in IL1RN and novel deletion c.2558+149_2558+203del54 in SLC4A11 were observed significantly more frequently in family members with KTCN (P = 0.004525 and P = 0.00761, respectively), suggesting involvement of these two genes in KTCN etiology in the studied family.
authors: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors: Dorota M
authors: DM
authors: Nowak
authors: Justyna A
authors: JA
authors: Karolak
authors: Joanna
authors: J
authors: Kubiak
authors: Marta
authors: M
authors: Gut
authors: Jose A
authors: JA
authors: Pitarque
authors: Andrea
authors: A
authors: Molinari
authors: Bassem A
authors: BA
authors: Bejjani
authors: Marzena
authors: M
authors: Gajecka
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D027321:Anion Transport Proteins / Q000235:genetics*; D017920:Antiporters / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D004252:DNA Mutational Analysis; D004484:Ecuador; D008040:Genetic Linkage; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D007640:Keratoconus / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; C425809:SLC4A11 protein, human