title: BIGH3 mutation spectrum in corneal dystrophies.
abstract: OBJECTIVE
  To investigate the molecular pathology underlying BIGH3-related corneal dystrophies (CDs) and to further delineate genotype-phenotype specificity.
  
  
  METHODS
  Sixty-one index patients with CDs were subjected to phenotypic and genotypic characterization. The corneal phenotypes of all patients were assessed by biomicroscopy and documented by slit lamp photography. The BIGH3 gene was amplified exon by exon from constitutional DNA to perform single-strand conformation polymorphism (SSCP) analysis, followed by direct bidirectional sequencing of abnormal conformers.
  
  
  RESULTS
  The phenotypes of CDs were classified as lattice CD in 30 patients, Groenouw type I in 12 (CDGGI), Avellino in 7 (CDA), Reis-Bückler in 8 (CDRB), and Thiel-Behnke in 4 (CDTB). Fifty occurrences of 16 distinct mutations were identified, including 8 novel mutations responsible for lattice type IIIA in three patients (CDLIIA), intermediate type I/IIIA (CDLI/IIIA) in four patients, and atypical CDL with deep deposits in one patient (CDL-deep).
  
  
  CONCLUSIONS
  Disease-causing mutations were identified in 80% of the patients (50/61). All mutations localize in two regions of kerato-epithelin: the amino acid R124 and BIGH3 fasc domain 4. This study also confirms the mutation hot spot at positions R124 and R555 with nearly 50% of the mutations targeting these two amino acids (24/50). In addition the corneal phenotypes induced by changes at R124 and R555 are amino acid specific: R124C in CDLI, R555W and R124S in CDGGI, R124H in CDA, R124L in CRRB, and R555Q in CDTB. In CDLIIIA, CDLI/IIIA, and CDL-deep the genotype-phenotype correlation is domain specific, with all changes occurring at the boundary or within the fasc4 domain.
authors.affiliation: Hôpital Jules Gonin, Department of Ophthalmology, Lausanne, Switzerland. francis.munier@chuv.hospvd.ch
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: Beatrice E
authors.initials: BE
authors.lastname: Frueh
authors.forename: Philippe
authors.initials: P
authors.lastname: Othenin-Girard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Uffer
authors.forename: Pascal
authors.initials: P
authors.lastname: Cousin
authors.forename: Ming X
authors.initials: MX
authors.lastname: Wang
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasi
authors.forename: Emilio
authors.initials: E
authors.lastname: Balestrazzi
authors.forename: Birgit
authors.initials: B
authors.lastname: Lorenz
authors.forename: Rafael
authors.initials: R
authors.lastname: Escoto
authors.forename: Rafael
authors.initials: R
authors.lastname: Barraquer
authors.forename: Maria
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: Balder
authors.initials: B
authors.lastname: Gloor
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fossarello
authors.forename: Arun D
authors.initials: AD
authors.lastname: Singh
authors.forename: Yvan
authors.initials: Y
authors.lastname: Arsenijevic
authors.forename: Léonidas
authors.initials: L
authors.lastname: Zografos
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000595:Amino Acid Sequence; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D016326:Extracellular Matrix Proteins; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D016212:Transforming Growth Factor beta / Q000235:genetics; D000099222:betaIG-H3 Protein
chemical_list: D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein