Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration

Autoren

Marcus Karlstetter
Nasrin Sorusch
Albert Caramoy
Katharina Dannhausen
Alexander Aslanidis
Sascha Fauser
Michael R Boesl
Kerstin Nagel-Wolfrum
Ernst R Tamm
Herbert Jägle
Heidi Stoehr
Uwe Wolfrum
Thomas Langmann

DOI

10.1093/hmg/ddu242

eISSN

1460-2083

ISSN

0964-6906

Ausgabe der Veröffentlichung

19

Zeitschrift

Human Molecular Genetics

Sprache

en

Online publication date

2014

Paginierung

5197 - 5210

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Oxford University Press (OUP)

Herausgeber URL

http://dx.doi.org/10.1093/hmg/ddu242

Datum der Datenerfassung

2017

Titel

Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration

Ausgabe der Zeitschrift

23

Data source: Crossref

Abstract

Mutations in the FAM161A gene were previously identified as the cause for autosomal-recessive retinitis pigmentosa 28. To study the effects of Fam161a dysfunction in vivo, we generated gene-trapped Fam161a(GT/GT) mice with a disruption of its C-terminal domain essential for protein-protein interactions. We confirmed the absence of the full-length Fam161a protein in the retina of Fam161a(GT/GT) mice using western blots and showed weak expression of a truncated Fam161a protein by immunohistochemistry. Histological analyses demonstrated that photoreceptor segments were disorganized in young Fam161a(GT/GT) mice and that the outer retina was completely lost at 6 months of age. Reactive microglia appeared in the outer retina and electroretinography showed an early loss of photoreceptor function in 4-month-old Fam161a(GT/GT) animals. Light and electron microscopy revealed a remarkable phenotype of a significantly shortened connecting cilium, spread ciliary microtubule doublets and disturbed disk organization in Fam161a(GT/GT) photoreceptor cells. Co-immunolabeling experiments demonstrated reduced expression and mislocalization of centrin 3 and disturbed targeting of the Fam161a interactors lebercilin and Cep290, which were restricted to the basal body and proximal connecting cilium in Fam161a(GT/GT) retinas. Moreover, we identified misrouting of the outer segment cargo proteins opsin and rds/peripherin 2 in Fam161a(GT/GT) mice. In conclusion, our results suggest a critical role for the C-terminal domain of Fam161a for molecular interactions and integrity of the connecting cilium. Fam161a is required for the molecular delivery into the outer segment cilium, a function which is essential for outer segment disk formation and ultimately visual function.

Addresses

Department of Ophthalmology, University of Cologne, Cologne, Germany.

Autoren

Marcus Karlstetter
Nasrin Sorusch
Albert Caramoy
Katharina Dannhausen
Alexander Aslanidis
Sascha Fauser
Michael R Boesl
Kerstin Nagel-Wolfrum
Ernst R Tamm
Herbert Jägle
Heidi Stoehr
Uwe Wolfrum
Thomas Langmann

DOI

10.1093/hmg/ddu242

eISSN

1460-2083

Externe Identifier

PubMed Identifier: 24833722

Open access

false

ISSN

0964-6906

Ausgabe der Veröffentlichung

19

Zeitschrift

Human molecular genetics

Schlüsselwörter

Microglia
Retina
Animals
Mice, Transgenic
Humans
Mice
Vision Disorders
Retinal Degeneration
Carrier Proteins
Eye Proteins
Gene Targeting
Gene Expression
Protein Binding
Protein Transport
Action Potentials
Genotype
Mutation
Female
Male
Photoreceptor Cells
Retinal Pigment Epithelium
Genetic Loci

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

5197 - 5210

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2014

Titel

Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

23

Data source: Europe PubMed Central

Abstract

Mutations in the FAM161A gene were previously identified as the cause for autosomal-recessive retinitis pigmentosa 28. To study the effects of Fam161a dysfunction in vivo, we generated gene-trapped Fam161a(GT/GT) mice with a disruption of its C-terminal domain essential for protein-protein interactions. We confirmed the absence of the full-length Fam161a protein in the retina of Fam161a(GT/GT) mice using western blots and showed weak expression of a truncated Fam161a protein by immunohistochemistry. Histological analyses demonstrated that photoreceptor segments were disorganized in young Fam161a(GT/GT) mice and that the outer retina was completely lost at 6 months of age. Reactive microglia appeared in the outer retina and electroretinography showed an early loss of photoreceptor function in 4-month-old Fam161a(GT/GT) animals. Light and electron microscopy revealed a remarkable phenotype of a significantly shortened connecting cilium, spread ciliary microtubule doublets and disturbed disk organization in Fam161a(GT/GT) photoreceptor cells. Co-immunolabeling experiments demonstrated reduced expression and mislocalization of centrin 3 and disturbed targeting of the Fam161a interactors lebercilin and Cep290, which were restricted to the basal body and proximal connecting cilium in Fam161a(GT/GT) retinas. Moreover, we identified misrouting of the outer segment cargo proteins opsin and rds/peripherin 2 in Fam161a(GT/GT) mice. In conclusion, our results suggest a critical role for the C-terminal domain of Fam161a for molecular interactions and integrity of the connecting cilium. Fam161a is required for the molecular delivery into the outer segment cilium, a function which is essential for outer segment disk formation and ultimately visual function.

Autoren

Marcus Karlstetter
Nasrin Sorusch
Albert Caramoy
Katharina Dannhausen
Alexander Aslanidis
Sascha Fauser
Michael R Boesl
Kerstin Nagel-Wolfrum
Ernst R Tamm
Herbert Jägle
Heidi Stoehr
Uwe Wolfrum
Thomas Langmann

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/24833722

DOI

10.1093/hmg/ddu242

eISSN

1460-2083

Ausgabe der Veröffentlichung

19

Zeitschrift

Hum Mol Genet

Schlüsselwörter

Action Potentials
Animals
Carrier Proteins
Eye Proteins
Female
Gene Expression
Gene Targeting
Genetic Loci
Genotype
Humans
Male
Mice
Mice, Transgenic
Microglia
Mutation
Photoreceptor Cells
Protein Binding
Protein Transport
Retina
Retinal Degeneration
Retinal Pigment Epithelium
Vision Disorders

Sprache

eng

Country

England

Paginierung

5197 - 5210

PII

hmg/ddu242

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

23

Data source: PubMed

Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration

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