Universität zu Köln

Karlstetter, Marcus, Sorusch, Nasrin, Caramoy, Albert, Dannhausen, Katharina, Aslanidis, Alexander, Fauser, Sascha, Boesl, Michael R., Nagel-Wolfrum, Kerstin, Tamm, Ernst R., Jaegle, Herbert, Stoehr, Heidi, Wolfrum, Uwe and Langmann, Thomas (2014). Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration. Hum. Mol. Genet., 23 (19). S. 5197 - 5211. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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 fulllength Fam161a protein in the retina of Fam161a(GTIGT) 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(GTIGT) 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. Fam 161a 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Karlstetter, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Sorusch, Nasrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Caramoy, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Dannhausen, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Aslanidis, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Boesl, Michael R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nagel-Wolfrum, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Tamm, Ernst R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaegle, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoehr, Heidi UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolfrum, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Langmann, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-427256
DOI:	10.1093/hmg/ddu242
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	23
Number:	19
Page Range:	S. 5197 - 5211
Date:	2014
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTRAFLAGELLAR TRANSPORT PROTEIN; EMBRYONIC STEM-CELLS; CONE PHOTORECEPTORS; CONNECTING CILIUM; TRANSITION ZONE; MOUSE; DEATH; MAINTENANCE; MUTATION; CEP290 Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42725