title: A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration.
abstract: The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.
authors.affiliation: Biochemistry Department, University of Otago, PO Box 56, Dunedin, New Zealand. marion.maw@stonebow.otago.ac.nz
authors.forename: M A
authors.initials: MA
authors.lastname: Maw
authors.forename: D
authors.initials: D
authors.lastname: Corbeil
authors.forename: J
authors.initials: J
authors.lastname: Koch
authors.forename: A
authors.initials: A
authors.lastname: Hellwig
authors.forename: J C
authors.initials: JC
authors.lastname: Wilson-Wheeler
authors.forename: R J
authors.initials: RJ
authors.lastname: Bridges
authors.forename: G
authors.initials: G
authors.lastname: Kumaramanickavel
authors.forename: S
authors.initials: S
authors.lastname: John
authors.forename: D
authors.initials: D
authors.lastname: Nancarrow
authors.forename: K
authors.initials: K
authors.lastname: Röper
authors.forename: A
authors.initials: A
authors.lastname: Weigmann
authors.forename: W B
authors.initials: WB
authors.lastname: Huttner
authors.forename: M J
authors.initials: MJ
authors.lastname: Denton
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD; D002462:Cell Membrane / Q000378:metabolism; D002894:Chromosomes, Human, Pair 4; D003241:Consanguinity; D005260:Female; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006023:Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007194:India; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010375:Pedigree; D010455:Peptides / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D017689:Polydactyly / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics*; D012374:Rod Cell Outer Segment / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D005819:Genetic Markers; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse