BIGH3 mutation spectrum in corneal dystrophies.
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.
Munier
Francis L
FL
Hôpital Jules Gonin, Department of Ophthalmology, Lausanne, Switzerland. francis.munier@chuv.hospvd.ch
Frueh
Beatrice E
BE
Othenin-Girard
Philippe
P
Uffer
Sylvie
S
Cousin
Pascal
P
Wang
Ming X
MX
Héon
Elise
E
Black
Graeme C M
GC
Blasi
Maria A
MA
Balestrazzi
Emilio
E
Lorenz
Birgit
B
Escoto
Rafael
R
Barraquer
Rafael
R
Hoeltzenbein
Maria
M
Gloor
Balder
B
Fossarello
Maurizio
M
Singh
Arun D
AD
Arsenijevic
Yvan
Y
Zografos
Léonidas
L
Schorderet
Daniel F
DF
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
D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein