title: Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice.
abstract: Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.
authors.affiliation: Department of Ophthalmology and Visual Science, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.forename: Concepcion
authors.initials: C
authors.lastname: Lillo
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.forename: Zhengya
authors.initials: Z
authors.lastname: Yu
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Martin
authors.initials: M
authors.lastname: Klein
authors.forename: Kim A
authors.initials: KA
authors.lastname: Howes
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kaminoh
authors.forename: Haoyu
authors.initials: H
authors.lastname: Chen
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Youssef Tawfik
authors.initials: YT
authors.lastname: Al-Sheikh
authors.forename: Goutam
authors.initials: G
authors.lastname: Karan
authors.forename: Denis
authors.initials: D
authors.lastname: Corbeil
authors.forename: Pascal
authors.initials: P
authors.lastname: Escher
authors.forename: Shin
authors.initials: S
authors.lastname: Kamaya
authors.forename: Chunmei
authors.initials: C
authors.lastname: Li
authors.forename: Samantha
authors.initials: S
authors.lastname: Johnson
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Changguan
authors.initials: C
authors.lastname: Wang
authors.forename: D Joshua
authors.initials: DJ
authors.lastname: Cameron
authors.forename: Wieland B
authors.initials: WB
authors.lastname: Huttner
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: Frances L
authors.initials: FL
authors.lastname: Munier
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: David M
authors.initials: DM
authors.lastname: Hunt
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000071916:AC133 Antigen; D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism; D004596:Electroretinography; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C442481:CDHR1 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse