Characterization of a Putative Founder Mutation that Accounts for the High Incidence of Cystinosis in Brittany

Cystinosis is an autosomal recessive disorder, char- acterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-90024del27, which has only been detected in families from this region. Reverse transcription-PCR amplifi- cation of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are pre- dicted to either severely truncate cystinosin or alter its topol- ogy, thus accounting for the severe phenotype of these indi- viduals. The mutation 898-90024del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cysti- nosis in Brittany. 1