A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration

The disks of vertebrate photoreceptors are produced by outgrowths of the pl asma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degeneratio ns, One such candidate is the gene encoding human prominin (mouse)-like 1 ( PROML1, previously known as AC133 antigen) which belongs to the prominin fa mily of 5-transmembrane domain proteins. Murine prominin (prom) shows a str ong preference for plasma membrane protrusions in a variety of epithelial c ells whereas PROML1 is expressed in retinoblastoma cell lines and adult ret ina. In the present study, molecular genetic analyses of a pedigree segrega ting for autosomal recessive retinal degeneration indicated that the affect ed individuals were homozygous for a nucleotide 1878 deletion in PROML1. Th is alteration is predicted to result in a frameshift at codon 614 with prem ature termination of translation. Expression of a similar prom deletion mut ant in CHO cells indicated that the truncated protein does not reach the ce ll surface. Immunocytochemistry revealed that prom is concentrated in the p lasma membrane evaginations at the base of the outer segments of rod photor eceptors. These findings suggest that loss of prominin causes retinal degen eration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.