Molecular genetic heterogeneity in autosomal dominant drusen

Objective - Autosomal dominant drusen is of particular interest because of its phenotypic similarity to age related macular degeneration. Currently, m utation R345W of EFEMP1 and, in a single pedigree, linkage to chromosome 6q 14 have been causally related to the disease. We proposed to investigate an d quantify the roles of EFEMP1 and the 6q14 locus in dominant drusen patien ts from the UK and USA. Design - Molecular genetic analysis. Participants - Ten unrelated families and 17 young drusen patients. Main outcome measures - Exons 1 and 2 of EFEMP1 were characterised by 5 ' r apid amplification of cDNA ends and direct sequencing. Exons 1-12 of EFEMP1 were then investigated for mutation by direct sequencing. A HpaII restrict ion digest test was constructed to detect the EFEMP1 R345W mutation. Marker loci spanning the two dominant drusen linked loci were used to generate ha plotype data, Results - Only seven of the 10 families (70%) and one of the 17 sporadic pa tients (6%) had the R345W mutation. The HpaII restriction digest test was f ound to be a reliable and quick method for detecting this. No other exonic or splice site mutation was identified. Of the three families without EFEMP 1 mutation, two were linked to the 2p16 region. Conclusions - EFEMP1 R345W accounts for only a proportion of the dominant d rusen phenotype. Importantly, other families linked to chromosome 2p16 rais e the possibility of EFEMP1 promoter sequence mutation or a second dominant drusen gene at this locus. Preliminary haplotype data suggest that the dis ease gene at the 6q14 locus is responsible for only a minority of dominant drusen cases.