Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice.
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.
Yang
Zhenglin
Z
Department of Ophthalmology and Visual Science, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
Chen
Yali
Y
Lillo
Concepcion
C
Chien
Jeremy
J
Yu
Zhengya
Z
Michaelides
Michel
M
Klein
Martin
M
Howes
Kim A
KA
Li
Yang
Y
Kaminoh
Yuuki
Y
Chen
Haoyu
H
Zhao
Chao
C
Chen
Yuhong
Y
Al-Sheikh
Youssef Tawfik
YT
Karan
Goutam
G
Corbeil
Denis
D
Escher
Pascal
P
Kamaya
Shin
S
Li
Chunmei
C
Johnson
Samantha
S
Frederick
Jeanne M
JM
Zhao
Yu
Y
Wang
Changguan
C
Cameron
D Joshua
DJ
Huttner
Wieland B
WB
Schorderet
Daniel F
DF
Munier
Frances L
FL
Moore
Anthony T
AT
Birch
David G
DG
Baehr
Wolfgang
W
Hunt
David M
DM
Williams
David S
DS
Zhang
Kang
K
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
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