title: Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function.
abstract: BACKGROUND
  Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described.
  
  
  METHODS
  In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein.
  
  
  CONCLUSIONS
  We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana.
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark. laura.kirstine.soenderberg.roos@regionh.dk.
authors.forename: Laura
authors.initials: L
authors.lastname: Roos
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark. birgitte.bertelsen@regionh.dk.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Bertelsen
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet Build. 207, DK-2800, Kgs. Lyngby, Denmark. ph@kemi.dtu.dk.
authors.forename: Pernille
authors.initials: P
authors.lastname: Harris
authors.affiliation: Department of Dermatology, Odense University Hospital, Odense, Denmark. Anette.Bygum@rsyd.dk.
authors.forename: Anette
authors.initials: A
authors.lastname: Bygum
authors.affiliation: Eye Clinic, Department of Ophthalmology, Copenhagen University Hospital, Glostrup, Denmark. hanne.jensen.08@regionh.dk.
authors.forename: Hanne
authors.initials: H
authors.lastname: Jensen
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark. karen.groenskov@regionh.dk.
authors.forename: Karen
authors.initials: K
authors.lastname: Grønskov
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark. Asuman.zeynep.tuemer@regionh.dk.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
mesh_terms: D000328:Adult; D001483:Base Sequence; D002648:Child; D003315:Cornea / Q000002:abnormalities*; D003316:Corneal Diseases / Q000235:genetics*; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005260:Female; D006801:Humans; D006956:Hyperopia / Q000235:genetics*; D007039:Hypotrichosis / Q000235:genetics*; D008297:Male; D008956:Models, Chemical; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011487:Protein Conformation; D011509:Proteoglycans / Q000737:chemistry* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014421:Turkey; D055815:Young Adult
chemical_list: C490948:KERA protein, human; D011509:Proteoglycans