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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 |
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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>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.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2013.06.003</identifier><identifier>PMID: 23849777</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>American journal of human genetics, 2013-08, Vol.93 (2), p.321-329</ispartof><rights>2013 The American Society of Human Genetics</rights><rights>Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Cell Press Aug 8, 2013</rights><rights>2013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2013 The American Society of Human Genetics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-8d1efa108446b9381f8127f33111f2722cc4623cd156d5af21f1bc4fcc54fbbe3</citedby><cites>FETCH-LOGICAL-c483t-8d1efa108446b9381f8127f33111f2722cc4623cd156d5af21f1bc4fcc54fbbe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738823/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738823/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23849777$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Davidson, Alice E.</creatorcontrib><creatorcontrib>Schwarz, Nele</creatorcontrib><creatorcontrib>Zelinger, Lina</creatorcontrib><creatorcontrib>Stern-Schneider, Gabriele</creatorcontrib><creatorcontrib>Shoemark, Amelia</creatorcontrib><creatorcontrib>Spitzbarth, Benjamin</creatorcontrib><creatorcontrib>Gross, Menachem</creatorcontrib><creatorcontrib>Laxer, Uri</creatorcontrib><creatorcontrib>Sosna, Jacob</creatorcontrib><creatorcontrib>Sergouniotis, Panagiotis I.</creatorcontrib><creatorcontrib>Waseem, Naushin H.</creatorcontrib><creatorcontrib>Wilson, Robert</creatorcontrib><creatorcontrib>Kahn, Richard A.</creatorcontrib><creatorcontrib>Plagnol, Vincent</creatorcontrib><creatorcontrib>Wolfrum, Uwe</creatorcontrib><creatorcontrib>Banin, Eyal</creatorcontrib><creatorcontrib>Hardcastle, Alison J.</creatorcontrib><creatorcontrib>Cheetham, Michael E.</creatorcontrib><creatorcontrib>Sharon, Dror</creatorcontrib><creatorcontrib>Webster, Andrew R.</creatorcontrib><title>Mutations in ARL2BP, Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein, Cause Autosomal-Recessive Retinitis Pigmentosa</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><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.</description><subject>ADP-Ribosylation Factors - genetics</subject><subject>ADP-Ribosylation Factors - metabolism</subject><subject>Adult</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - metabolism</subject><subject>Eye diseases</subject><subject>Female</subject><subject>Genes, Recessive</subject><subject>Genetic disorders</subject><subject>Genomics</subject><subject>GTP-Binding Proteins - genetics</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Pedigree</subject><subject>Photoreceptor Cells - metabolism</subject><subject>Photoreceptor Cells - pathology</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Retina</subject><subject>Retinitis Pigmentosa - genetics</subject><subject>Retinitis Pigmentosa - metabolism</subject><subject>Retinitis Pigmentosa - pathology</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9kU1v1DAQhiMEokvhD3BAkbhwaILHzocjoUrbpQWkRaxWcLYcZ7J1SOxiOytV4sfj7ZYKOHDyYZ55xzNPkrwEkgOB6u2Qy-F6l1MCLCdVTgh7lCygZHVWVaR8nCwIITRraFOfJM-8HwgB4IQ9TU4o40VT1_Ui-fl5DjJoa3yqTbrcrunF5iy9NMp22uzS5ftNttWt9bfjHZVdSRWsy9b6O6Y0vdDmDts4G1Cbs3QlZ4_pcg7W20mO2RYVeq_3mG4xaKOD9ulG7yY0kZDPkye9HD2-uH9Pk29Xl19XH7P1lw-fVst1pgrOQsY7wF4C4UVRtQ3j0HOgdc8YAPS0plSpoqJMdVBWXSl7Cj20quiVKou-bZGdJufH3Ju5nbBTcbqTo7hxepLuVlipxd8Vo6_Fzu4FqxnnlMWAN_cBzv6Y0Qcxaa9wHKVBO3sBRVHwirASIvr6H3SwszNxvUhRaDjUZRkpeqSUs9477B8-A0Qc5IpBHOSKg1xBKhHlxqZXf67x0PLbZgTeHQGMx9xrdMIrjUZhpx2qIDqr_5f_C32etko</recordid><startdate>20130808</startdate><enddate>20130808</enddate><creator>Davidson, Alice E.</creator><creator>Schwarz, Nele</creator><creator>Zelinger, Lina</creator><creator>Stern-Schneider, Gabriele</creator><creator>Shoemark, Amelia</creator><creator>Spitzbarth, Benjamin</creator><creator>Gross, Menachem</creator><creator>Laxer, Uri</creator><creator>Sosna, Jacob</creator><creator>Sergouniotis, Panagiotis I.</creator><creator>Waseem, Naushin H.</creator><creator>Wilson, Robert</creator><creator>Kahn, Richard A.</creator><creator>Plagnol, Vincent</creator><creator>Wolfrum, Uwe</creator><creator>Banin, Eyal</creator><creator>Hardcastle, Alison J.</creator><creator>Cheetham, Michael E.</creator><creator>Sharon, Dror</creator><creator>Webster, Andrew R.</creator><general>Elsevier Inc</general><general>Cell Press</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130808</creationdate><title>Mutations in ARL2BP, Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein, Cause Autosomal-Recessive Retinitis Pigmentosa</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-8d1efa108446b9381f8127f33111f2722cc4623cd156d5af21f1bc4fcc54fbbe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>ADP-Ribosylation Factors - 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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>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.</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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