Homozygous CRYBB1 deletion mutation underlies autosomal recessive congenital cataract.
OBJECTIVE
Some 30% of cases of congenital cataract are genetic in origin, usually transmitted as an autosomal dominant trait. The molecular defects underlying some of these autosomal dominant cases have been identified and were demonstrated to be mostly mutations in crystallin genes. The autosomal recessive form of the disease is less frequent. To date, only four genes and three loci have been associated with autosomal recessive congenital cataract. Two extended unrelated consanguineous inbred Bedouin families from southern Israel presenting with autosomal recessive congenital nuclear cataract were studied.


METHODS
Assuming a founder effect, homozygosity testing was performed using polymorphic microsatellite markers adjacent to each of 32 candidate genes.


RESULTS
A locus on chromosome 22 surrounding marker D22S1167 demonstrated homozygosity only in affected individuals (lod score > 6.57 at theta = 0 for D22S1167). Two crystallin genes (CRYBB1 and CRYBA4) located within 0.1 cM on each side of this marker were sequenced. No mutations were found in CRYBA4. However, an identical homozygous delG168 mutation in exon 2 of CRYBB1 was discovered in affected individuals of both families, generating a frameshift leading to a missense protein sequence at amino acid 57 and truncation at amino acid 107 of the 252-amino-acid CRYBB1 protein. Denaturing [d]HPLC analysis of 100 Bedouin individuals unrelated to the affected families demonstrated no CRYBB1 mutations.


CONCLUSIONS
CRYBB1 mutations have been shown to underlie autosomal dominant congenital cataract. The current study showed that a different mutation in the same gene causes an autosomal recessive form of the disease.
Cohen
David
D
The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Bar-Yosef
Udy
U
Levy
Jaime
J
Gradstein
Libe
L
Belfair
Nadav
N
Ofir
Rivka
R
Joshua
Sarah
S
Lifshitz
Tova
T
Carmi
Rivka
R
Birk
Ohad S
OS
D001483:Base Sequence; D002386:Cataract / Q000151:congenital* / Q000235:genetics*; D002675:Child, Preschool; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation; D005808:Genes, Recessive; D008040:Genetic Linkage; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics; D038206:beta-Crystallin B Chain / Q000235:genetics*
C105601:CRYBB1 protein, human; D038206:beta-Crystallin B Chain