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Mutations in ARL2BP, Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein, Cause Autosomal-Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the smal...

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Published in:American journal of human genetics 2013-08, Vol.93 (2), p.321-329
Main Authors: Davidson, Alice E., Schwarz, Nele, Zelinger, Lina, Stern-Schneider, Gabriele, Shoemark, Amelia, Spitzbarth, Benjamin, Gross, Menachem, Laxer, Uri, Sosna, Jacob, Sergouniotis, Panagiotis I., Waseem, Naushin H., Wilson, Robert, Kahn, Richard A., Plagnol, Vincent, Wolfrum, Uwe, Banin, Eyal, Hardcastle, Alison J., Cheetham, Michael E., Sharon, Dror, Webster, Andrew R.
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cited_by cdi_FETCH-LOGICAL-c483t-8d1efa108446b9381f8127f33111f2722cc4623cd156d5af21f1bc4fcc54fbbe3
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container_title American journal of human genetics
container_volume 93
creator Davidson, Alice E.
Schwarz, Nele
Zelinger, Lina
Stern-Schneider, Gabriele
Shoemark, Amelia
Spitzbarth, Benjamin
Gross, Menachem
Laxer, Uri
Sosna, Jacob
Sergouniotis, Panagiotis I.
Waseem, Naushin H.
Wilson, Robert
Kahn, Richard A.
Plagnol, Vincent
Wolfrum, Uwe
Banin, Eyal
Hardcastle, Alison J.
Cheetham, Michael E.
Sharon, Dror
Webster, Andrew R.
description Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101−1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.
doi_str_mv 10.1016/j.ajhg.2013.06.003
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Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101−1G&gt;C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T&gt;G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. 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This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23849777</pmid><doi>10.1016/j.ajhg.2013.06.003</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects ADP-Ribosylation Factors - genetics
ADP-Ribosylation Factors - metabolism
Adult
Animals
Base Sequence
Carrier Proteins - genetics
Carrier Proteins - metabolism
Epithelial Cells - cytology
Epithelial Cells - metabolism
Eye diseases
Female
Genes, Recessive
Genetic disorders
Genomics
GTP-Binding Proteins - genetics
GTP-Binding Proteins - metabolism
Homozygote
Humans
Male
Mice
Molecular Sequence Data
Mutation
Pedigree
Photoreceptor Cells - metabolism
Photoreceptor Cells - pathology
Protein Binding
Proteins
Retina
Retinitis Pigmentosa - genetics
Retinitis Pigmentosa - metabolism
Retinitis Pigmentosa - pathology
Ribonucleic acid
RNA
title Mutations in ARL2BP, Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein, Cause Autosomal-Recessive Retinitis Pigmentosa
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