Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders
Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these diso...
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| creator | Thiadens, Alberta A.H.J. den Hollander, Anneke I. Roosing, Susanne Nabuurs, Sander B. Zekveld-Vroon, Renate C. Collin, Rob W.J. De Baere, Elfride Koenekoop, Robert K. van Schooneveld, Mary J. Strom, Tim M. van Lith-Verhoeven, Janneke J.C. Lotery, Andrew J. van Moll-Ramirez, Norka Leroy, Bart P. van den Born, L. Ingeborgh Hoyng, Carel B. Cremers, Frans P.M. Klaver, Caroline C.W. |
| description | Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes. |
| doi_str_mv | 10.1016/j.ajhg.2009.06.016 |
| format | Article |
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Ingeborgh ; Hoyng, Carel B. ; Cremers, Frans P.M. ; Klaver, Caroline C.W.</creator><creatorcontrib>Thiadens, Alberta A.H.J. ; den Hollander, Anneke I. ; Roosing, Susanne ; Nabuurs, Sander B. ; Zekveld-Vroon, Renate C. ; Collin, Rob W.J. ; De Baere, Elfride ; Koenekoop, Robert K. ; van Schooneveld, Mary J. ; Strom, Tim M. ; van Lith-Verhoeven, Janneke J.C. ; Lotery, Andrew J. ; van Moll-Ramirez, Norka ; Leroy, Bart P. ; van den Born, L. Ingeborgh ; Hoyng, Carel B. ; Cremers, Frans P.M. ; Klaver, Caroline C.W.</creatorcontrib><description>Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2009.06.016</identifier><identifier>PMID: 19615668</identifier><identifier>CODEN: AJHGAG</identifier><language>eng</language><publisher>Cambridge, MA: Elsevier Inc</publisher><subject>Base Sequence ; Biological and medical sciences ; Case-Control Studies ; Chromosome Mapping ; Chromosomes, Human, Pair 10 ; Classical genetics, quantitative genetics, hybrids ; Color Vision Defects - genetics ; Comparative analysis ; Consanguinity ; Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics ; Electroretinography ; Eye Proteins - genetics ; Female ; Frameshift Mutation ; Fundamental and applied biological sciences. Psychology ; General aspects. Genetic counseling ; Genes ; Genes, Recessive ; Genetic disorders ; Genetics of eukaryotes. Biological and molecular evolution ; Genome-Wide Association Study ; Genomics ; Genotype & phenotype ; Homozygote ; Human ; Humans ; Male ; Medical genetics ; Medical sciences ; Middle Aged ; Molecular and cellular biology ; Molecular Sequence Data ; Mutation ; Mutation, Missense ; Pedigree ; Polymorphism, Single Nucleotide ; Retinal Cone Photoreceptor Cells - enzymology ; Retinal Cone Photoreceptor Cells - physiology ; Tomography</subject><ispartof>American journal of human genetics, 2009-08, Vol.85 (2), p.240-247</ispartof><rights>2009 The American Society of Human Genetics</rights><rights>2009 INIST-CNRS</rights><rights>Copyright University of Chicago, acting through its Press Aug 14, 2009</rights><rights>2009 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2009 The American Society of Human Genetics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-681b9bbfb405a901955c5064b1509961649a231f2cbefb3c68e9e9f7005070303</citedby><cites>FETCH-LOGICAL-c541t-681b9bbfb405a901955c5064b1509961649a231f2cbefb3c68e9e9f7005070303</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/PMC2725240/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ajhg.2009.06.016$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,3552,27931,27932,46002,53798,53800</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21830509$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19615668$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thiadens, Alberta A.H.J.</creatorcontrib><creatorcontrib>den Hollander, Anneke I.</creatorcontrib><creatorcontrib>Roosing, Susanne</creatorcontrib><creatorcontrib>Nabuurs, Sander B.</creatorcontrib><creatorcontrib>Zekveld-Vroon, Renate C.</creatorcontrib><creatorcontrib>Collin, Rob W.J.</creatorcontrib><creatorcontrib>De Baere, Elfride</creatorcontrib><creatorcontrib>Koenekoop, Robert K.</creatorcontrib><creatorcontrib>van Schooneveld, Mary J.</creatorcontrib><creatorcontrib>Strom, Tim M.</creatorcontrib><creatorcontrib>van Lith-Verhoeven, Janneke J.C.</creatorcontrib><creatorcontrib>Lotery, Andrew J.</creatorcontrib><creatorcontrib>van Moll-Ramirez, Norka</creatorcontrib><creatorcontrib>Leroy, Bart P.</creatorcontrib><creatorcontrib>van den Born, L. Ingeborgh</creatorcontrib><creatorcontrib>Hoyng, Carel B.</creatorcontrib><creatorcontrib>Cremers, Frans P.M.</creatorcontrib><creatorcontrib>Klaver, Caroline C.W.</creatorcontrib><title>Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.</description><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Case-Control Studies</subject><subject>Chromosome Mapping</subject><subject>Chromosomes, Human, Pair 10</subject><subject>Classical genetics, quantitative genetics, hybrids</subject><subject>Color Vision Defects - genetics</subject><subject>Comparative analysis</subject><subject>Consanguinity</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics</subject><subject>Electroretinography</subject><subject>Eye Proteins - genetics</subject><subject>Female</subject><subject>Frameshift Mutation</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>General aspects. Genetic counseling</subject><subject>Genes</subject><subject>Genes, Recessive</subject><subject>Genetic disorders</subject><subject>Genetics of eukaryotes. 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Ingeborgh</creator><creator>Hoyng, Carel B.</creator><creator>Cremers, Frans P.M.</creator><creator>Klaver, Caroline C.W.</creator><general>Elsevier Inc</general><general>Cell Press</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>20090814</creationdate><title>Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders</title><author>Thiadens, Alberta A.H.J. ; den Hollander, Anneke I. ; Roosing, Susanne ; Nabuurs, Sander B. ; Zekveld-Vroon, Renate C. ; Collin, Rob W.J. ; De Baere, Elfride ; Koenekoop, Robert K. ; van Schooneveld, Mary J. ; Strom, Tim M. ; van Lith-Verhoeven, Janneke J.C. ; Lotery, Andrew J. ; van Moll-Ramirez, Norka ; Leroy, Bart P. ; van den Born, L. 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We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.</abstract><cop>Cambridge, MA</cop><pub>Elsevier Inc</pub><pmid>19615668</pmid><doi>10.1016/j.ajhg.2009.06.016</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0002-9297 |
| ispartof | American journal of human genetics, 2009-08, Vol.85 (2), p.240-247 |
| issn | 0002-9297 1537-6605 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2725240 |
| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via ScienceDirect (Elsevier); PubMed Central |
| subjects | Base Sequence Biological and medical sciences Case-Control Studies Chromosome Mapping Chromosomes, Human, Pair 10 Classical genetics, quantitative genetics, hybrids Color Vision Defects - genetics Comparative analysis Consanguinity Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics Electroretinography Eye Proteins - genetics Female Frameshift Mutation Fundamental and applied biological sciences. Psychology General aspects. Genetic counseling Genes Genes, Recessive Genetic disorders Genetics of eukaryotes. Biological and molecular evolution Genome-Wide Association Study Genomics Genotype & phenotype Homozygote Human Humans Male Medical genetics Medical sciences Middle Aged Molecular and cellular biology Molecular Sequence Data Mutation Mutation, Missense Pedigree Polymorphism, Single Nucleotide Retinal Cone Photoreceptor Cells - enzymology Retinal Cone Photoreceptor Cells - physiology Tomography |
| title | Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-05T05%3A43%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Homozygosity%20Mapping%20Reveals%20PDE6C%20Mutations%20in%20Patients%20with%20Early-Onset%20Cone%20Photoreceptor%20Disorders&rft.jtitle=American%20journal%20of%20human%20genetics&rft.au=Thiadens,%20Alberta%20A.H.J.&rft.date=2009-08-14&rft.volume=85&rft.issue=2&rft.spage=240&rft.epage=247&rft.pages=240-247&rft.issn=0002-9297&rft.eissn=1537-6605&rft.coden=AJHGAG&rft_id=info:doi/10.1016/j.ajhg.2009.06.016&rft_dat=%3Cproquest_pubme%3E1836651481%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=219602574&rft_id=info:pmid/19615668&rft_els_id=S0002929709002523&rfr_iscdi=true |