Primary congenital glaucoma and Rieger's anomaly: extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations.
OBJECTIVE
Mutations in the cytochrome P450 1B1 (CYP1B1) gene are a frequent cause of primary congenital glaucoma (PCG) in different ethnic groups. Cytochrome P450 proteins are monooxygenases, which catalyze many reactions involved in the metabolism of drugs as well as steroids and other lipids. The repeated occurence of several mutations in various ethnic groups raises the question if founder effects or mutation-prone sites in CYP1B1 are the cause for this observation.


METHODS
A total of 30 individuals (26 PCG patients, three Rieger's anomaly patients, and one variant carrier), presenting 17 variants in CYP1B1 (15 mutations and two variations) were included in our study. We sequenced the entire genomic region of CYP1B1 and analyzed microsatellites flanking the gene in all individuals and constructed haplotypes for all variations using a combination of single nucleotide polymorphisms and microsatellites.


RESULTS
For the CYP1B1 genomic region, we identified five extended haplotypes associated with 17 variations. These haplotypes were complemented with microsatellite information from the region surrounding this gene. A total of eight CYP1B1 mutations were found more than once, each of them presenting one identical haplotype in different individuals. Six mutations were represented in different ethnic groups.


CONCLUSIONS
Our results confirm founder effects for most of CYP1B1 mutations. Most of these mutations must have occurred as unique events in the past.
Chavarria-Soley
Gabriela
G
Institute of Human Genetics, Friedrich-Alexander-University, Erlangen, Germany.
Michels-Rautenstrauss
Karin
K
Pasutto
Francesca
F
Flikier
David
D
Flikier
Paul
P
Cirak
Sebahattin
S
Bejjani
Bassem
B
Winters
Daniel L
DL
Lewis
Richard A
RA
Mardin
Christian
C
Reis
Andre
A
Rautenstrauss
Bernd
B
D000869:Anterior Eye Segment / Q000002:abnormalities*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D065633:Cytochrome P-450 CYP1B1; D005124:Eye Abnormalities / Q000235:genetics*; D018703:Founder Effect; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation
D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1