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.

Prominin-2 is a novel marker of distal tubules and collecting ducts of the human and murine kidney

“…Indeed, prominin-1 has been detected on the apical (luminal) side of various developing and adult epithelia found in both, mouse and human organs (Corbeil et al 1998Fargeas et al 2004;Jászai et al 2007bJászai et al , 2008Lardon et al 2008;Karbanová et al 2008;reviewed in Fargeas et al 2006) including the kidney where it is expressed in proximal nephron tubules and parietal layer of the Bowman's capsule (Weigmann et al 1997;Florek et al 2005). Moreover, its expression is documented in nonepithelial cells such as photoreceptor and glial cells (Maw et al 2000;Yang et al 2008;Zacchigna et al 2009;Corbeil et al 2009). …”

Rhodopsin Trafficking and Mistrafficking

“…113 F-actins interact with prominin-1 and photoreceptor-specific cadherin (PCDH21), both of which are located in nascent disks and appear to play critical roles in disk morphogenesis. [114][115][116][117] When F-actin filaments are disrupted with cytochalasin D treatment, evaginations do not seal and instead overgrow. 101 This overgrowth is due to the failure of sealing the evaginations by the phototransductive plasma membrane domain which contains cGMP-gated channel.…”

“…Mutations in the gene encoding cGMP-gated channel beta subunit and GARP proteins lead to malformation and enlargement of the disk membrane 126 : a phenotype similar to that observed in prominin-1-deficient rod photoreceptors. 116 Therefore, the formation of disks is dependent on the formation of the phototransductive plasma membrane.…”

Cross species analysis of Prominin reveals a conserved cellular role in invertebrate and vertebrate photoreceptor cells

“…S3A). In a heterozygous condition hProm1 (R373C) results in a form of macular degeneration in humans and expression of this allele in a wild-type background in mice results in a complete disruption of disc morphogenesis (Yang et al, 2008). Nonetheless, how this protein induces degeneration is not clear.…”

“…With respect to ciliated photoreceptor cells, Prominin1 localizes to the membrane extensions that give rise to the membrane discs of the outer segment phototransduction compartment (Han et al, 2012;Maw et al, 2000). Furthermore, directed murine knock-out of Prominin1 and analyses of several inherited human retinopathies have demonstrated an essential role for Prominin1 in generating and maintaining the integrity of the photoreceptor cell outer segment (Kleinman and Ambati, 2008;Maw et al, 2000;Yang et al, 2008;Zacchigna et al, 2009). In rhabdomeric photoreceptors, Drosophila Prominin localizes to the tips of the microvilli that create the rhabdomere and removal disrupts the morphology and organization of the phototransduction compartment (Zelhof et al, 2006).…”