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S-cone syndrome (ESCS) is an unusual disease of photoreceptors that includes night blindness (suggestive of rod dysfunction), an abnormal electroretinogram (ERG) with a waveform that is nearly identical under both light and dark adaptation, and an increased sensitivity of the ERG to short-wavelength light [1,2]. The disease is caused by mutations in the orphan nuclear receptor transcription factor NR2E3 (also known as photoreceptor nuclear receptor), which is expressed exclusively in rods [3,4]. Recent human genetic studies have also demonstrated mutations in this gene in Goldmann-Favre syndrome and many cases of clumped pigmentary retinal degeneration [5].\nThe initial reports of patients with ESCS attributed the unusual ERG to an abnormally functioning rod photoreceptor system with persistent activity under light adaptation [6–8]. Subsequent studies, however, concluded that the ERG was due to supernumerary short-wavelength (“blue”) cone photoreceptors (S-cones) in these patients [1,2,9–11]. Histopathologic analysis of a retina from a human patient with ESCS and extensive retinal degeneration demonstrated an absence of rhodopsin-positive cells and an increase in the number of S-cone opsin-expressing cells. Nevertheless, the overall density of cones was only modestly increased in this patient (approximately 2-fold), suggesting that there might be additional factors that contribute to the very large, light-adapted ERG seen in this disease. In addition to the ERG findings, patients with ESCS have dysmorphic retinas with rosette formation in the outer nuclear layer (ONL) where photoreceptor cell bodies reside, and a slow retinal degeneration that can ultimately lead to complete blindness [12–14].\nMutations in the mouse ortholog of NR2E3 have been identified in the spontaneous mutant retinal degeneration 7 (rd7) [15]. This mutant demonstrates slow retinal degeneration and abnormal lamination of the ONL with rosette formation [15,16]. Curiously, the ERG of the mouse under both light and dark adaptation has been reported to be normal, showing progressive attenuation with time, presumably due to degenerative cell loss [15]. A prior study showed a 2- to 3-fold increase in the number S-opsin–positive cells in the rd7 retina compared to wild type [17]. In addition, two groups recently reported derepression of additional cone genes in the rd7 mutant [18,19].\nIn order to better understand the mechanistic basis of ESCS, we undertook a molecular and ultrastructural analysis of the photoreceptors of the rd7 mutant mouse. Microarray and in situ hybridization analyses revealed a modest increase in the number of S-opsin–positive cells and widespread derepression of many cone-specific genes within rod photoreceptor cells. Ultrastructural studies demonstrated that the cells that coexpress rod and cone genes in the rd7 retina represent a morphologically hybrid cell type, intermediate between normal rods and cones."}

{"project":"craft-ca-core-ex-dev","denotations":[{"id":"T620","span":{"begin":24,"end":28},"obj":"CL:0000573"},{"id":"T621","span":{"begin":70,"end":84},"obj":"CL:0000210"},{"id":"T622","span":{"begin":130,"end":133},"obj":"CL:0000604"},{"id":"T623","span":{"begin":246,"end":261},"obj":"GO:1990603"},{"id":"T624","span":{"begin":361,"end":370},"obj":"SO_EXT:sequence_alteration_entity_or_process"},{"id":"T625","span":{"begin":378,"end":384},"obj":"SO:0000910"},{"id":"T626","span":{"begin":385,"end":392},"obj":"GO:0005634"},{"id":"T627","span":{"begin":393,"end":401},"obj":"GO_EXT:0004872"},{"id":"T628","span":{"begin":402,"end":415},"obj":"GO_EXT:transcription"},{"id":"T629","span":{"begin":402,"end":422},"obj":"GO_EXT:transcription_factor"},{"id":"T630","span":{"begin":423,"end":428},"obj":"PR_EXT:000011403"},{"id":"T631","span":{"begin":444,"end":457},"obj":"CL:0000210"},{"id":"T632","span":{"begin":444,"end":474},"obj":"PR_EXT:000011403"},{"id":"T633","span":{"begin":458,"end":465},"obj":"GO:0005634"},{"id":"T634","span":{"begin":466,"end":474},"obj":"GO_EXT:0004872"},{"id":"T635","span":{"begin":486,"end":495},"obj":"GO:0010467"},{"id":"T636","span":{"begin":511,"end":515},"obj":"CL:0000604"},{"id":"T637","span":{"begin":530,"end":535},"obj":"NCBITaxon:9606"},{"id":"T638","span":{"begin":536,"end":543},"obj":"SO_EXT:0000704"},{"id":"T639","span":{"begin":575,"end":584},"obj":"SO_EXT:sequence_alteration_entity_or_process"},{"id":"T640","span":{"begin":593,"end":597},"obj":"SO_EXT:0000704"},{"id":"T641","span":{"begin":651,"end":661},"obj":"CHEBI_EXT:26130"},{"id":"T642","span":{"begin":662,"end":669},"obj":"UBERON:0000966"},{"id":"T643","span":{"begin":786,"end":803},"obj":"CL:0000604"},{"id":"T644","span":{"begin":962,"end":966},"obj":"_FRAGMENT"},{"id":"T645","span":{"begin":974,"end":988},"obj":"CL:0000495"},{"id":"T646","span":{"begin":969,"end":988},"obj":"CL:0000573"},{"id":"T647","span":{"begin":992,"end":997},"obj":"CL:0000573"},{"id":"T648","span":{"begin":1059,"end":1065},"obj":"UBERON:0000966"},{"id":"T649","span":{"begin":1073,"end":1078},"obj":"NCBITaxon:9606"},{"id":"T650","span":{"begin":1111,"end":1118},"obj":"UBERON:0000966"},{"id":"T651","span":{"begin":1159,"end":1168},"obj":"PR_EXT:000001245"},{"id":"T652","span":{"begin":1178,"end":1183},"obj":"CL_GO_EXT:cell"},{"id":"T653","span":{"begin":1217,"end":1229},"obj":"PR_EXT:000001195"},{"id":"T654","span":{"begin":1219,"end":1223},"obj":"CL:0000573"},{"id":"T655","span":{"begin":1230,"end":1240},"obj":"GO:0010467"},{"id":"T656","span":{"begin":1241,"end":1246},"obj":"CL_GO_EXT:cell"},{"id":"T657","span":{"begin":1285,"end":1290},"obj":"CL:0000573"},{"id":"T658","span":{"begin":1552,"end":1559},"obj":"UBERON:0000966"},{"id":"T659","span":{"begin":1590,"end":1609},"obj":"UBERON:0001789"},{"id":"T660","span":{"begin":1596,"end":1603},"obj":"GO:0005634"},{"id":"T661","span":{"begin":1611,"end":1614},"obj":"UBERON:0001789"},{"id":"T662","span":{"begin":1622,"end":1635},"obj":"CL:0000210"},{"id":"T663","span":{"begin":1636,"end":1640},"obj":"CL_GO_EXT:cell"},{"id":"T664","span":{"begin":1636,"end":1647},"obj":"GO:0044297"},{"id":"T665","span":{"begin":1667,"end":1674},"obj":"UBERON:0000966"},{"id":"T666","span":{"begin":1744,"end":1753},"obj":"SO_EXT:sequence_alteration_entity_or_process"},{"id":"T667","span":{"begin":1761,"end":1766},"obj":"NCBITaxon:10088"},{"id":"T668","span":{"begin":1767,"end":1775},"obj":"SO_EXT:0000855"},{"id":"T669","span":{"begin":1779,"end":1784},"obj":"PR_EXT:000011403"},{"id":"T670","span":{"begin":1825,"end":1831},"obj":"SO_EXT:sequence_altered_entity_or_alteration_process"},{"id":"T671","span":{"begin":1832,"end":1839},"obj":"UBERON:0000966"},{"id":"T672","span":{"begin":1872,"end":1878},"obj":"SO_EXT:sequence_altered_entity"},{"id":"T673","span":{"begin":1897,"end":1904},"obj":"UBERON:0000966"},{"id":"T674","span":{"begin":1949,"end":1952},"obj":"UBERON:0001789"},{"id":"T675","span":{"begin":2011,"end":2016},"obj":"NCBITaxon:10088"},{"id":"T676","span":{"begin":2038,"end":2053},"obj":"GO:1990603"},{"id":"T677","span":{"begin":2160,"end":2164},"obj":"CL_GO_EXT:cell"},{"id":"T678","span":{"begin":2235,"end":2242},"obj":"PR_EXT:000001195"},{"id":"T679","span":{"begin":2252,"end":2257},"obj":"CL_GO_EXT:cell"},{"id":"T680","span":{"begin":2269,"end":2275},"obj":"UBERON:0000966"},{"id":"T681","span":{"begin":2288,"end":2297},"obj":"SO_EXT:wild_type_entity_or_quality"},{"id":"T682","span":{"begin":2373,"end":2377},"obj":"CL:0000573"},{"id":"T683","span":{"begin":2378,"end":2383},"obj":"SO_EXT:0000704"},{"id":"T684","span":{"begin":2395,"end":2401},"obj":"SO_EXT:sequence_altered_entity"},{"id":"T685","span":{"begin":2487,"end":2496},"obj":"CHEBI_EXT:polyatomic_entity_or_group"},{"id":"T686","span":{"begin":2533,"end":2547},"obj":"CL:0000210"},{"id":"T687","span":{"begin":2559,"end":2565},"obj":"SO_EXT:sequence_altered_entity_or_alteration_process"},{"id":"T688","span":{"begin":2566,"end":2571},"obj":"NCBITaxon:10088"},{"i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S-cone syndrome (ESCS) is an unusual disease of photoreceptors that includes night blindness (suggestive of rod dysfunction), an abnormal electroretinogram (ERG) with a waveform that is nearly identical under both light and dark adaptation, and an increased sensitivity of the ERG to short-wavelength light [1,2]. The disease is caused by mutations in the orphan nuclear receptor transcription factor NR2E3 (also known as photoreceptor nuclear receptor), which is expressed exclusively in rods [3,4]. Recent human genetic studies have also demonstrated mutations in this gene in Goldmann-Favre syndrome and many cases of clumped pigmentary retinal degeneration [5].\nThe initial reports of patients with ESCS attributed the unusual ERG to an abnormally functioning rod photoreceptor system with persistent activity under light adaptation [6–8]. Subsequent studies, however, concluded that the ERG was due to supernumerary short-wavelength (“blue”) cone photoreceptors (S-cones) in these patients [1,2,9–11]. Histopathologic analysis of a retina from a human patient with ESCS and extensive retinal degeneration demonstrated an absence of rhodopsin-positive cells and an increase in the number of S-cone opsin-expressing cells. Nevertheless, the overall density of cones was only modestly increased in this patient (approximately 2-fold), suggesting that there might be additional factors that contribute to the very large, light-adapted ERG seen in this disease. In addition to the ERG findings, patients with ESCS have dysmorphic retinas with rosette formation in the outer nuclear layer (ONL) where photoreceptor cell bodies reside, and a slow retinal degeneration that can ultimately lead to complete blindness [12–14].\nMutations in the mouse ortholog of NR2E3 have been identified in the spontaneous mutant retinal degeneration 7 (rd7) [15]. This mutant demonstrates slow retinal degeneration and abnormal lamination of the ONL with rosette formation [15,16]. Curiously, the ERG of the mouse under both light and dark adaptation has been reported to be normal, showing progressive attenuation with time, presumably due to degenerative cell loss [15]. A prior study showed a 2- to 3-fold increase in the number S-opsin–positive cells in the rd7 retina compared to wild type [17]. In addition, two groups recently reported derepression of additional cone genes in the rd7 mutant [18,19].\nIn order to better understand the mechanistic basis of ESCS, we undertook a molecular and ultrastructural analysis of the photoreceptors of the rd7 mutant mouse. Microarray and in situ hybridization analyses revealed a modest increase in the number of S-opsin–positive cells and widespread derepression of many cone-specific genes within rod photoreceptor cells. Ultrastructural studies demonstrated that the cells that coexpress rod and cone genes in the rd7 retina represent a morphologically hybrid cell type, intermediate between normal rods and cones."}

{"project":"craft-ca-core-dev","denotations":[{"id":"T557","span":{"begin":24,"end":28},"obj":"CL:0000573"},{"id":"T558","span":{"begin":70,"end":84},"obj":"CL:0000210"},{"id":"T559","span":{"begin":130,"end":133},"obj":"CL:0000604"},{"id":"T560","span":{"begin":246,"end":261},"obj":"GO:1990603"},{"id":"T561","span":{"begin":378,"end":384},"obj":"SO:0000910"},{"id":"T562","span":{"begin":385,"end":392},"obj":"GO:0005634"},{"id":"T563","span":{"begin":423,"end":428},"obj":"PR:000011403"},{"id":"T564","span":{"begin":444,"end":457},"obj":"CL:0000210"},{"id":"T565","span":{"begin":444,"end":474},"obj":"PR:000011403"},{"id":"T566","span":{"begin":458,"end":465},"obj":"GO:0005634"},{"id":"T567","span":{"begin":486,"end":495},"obj":"GO:0010467"},{"id":"T568","span":{"begin":511,"end":515},"obj":"CL:0000604"},{"id":"T569","span":{"begin":530,"end":535},"obj":"NCBITaxon:9606"},{"id":"T570","span":{"begin":536,"end":543},"obj":"SO:0000704"},{"id":"T571","span":{"begin":593,"end":597},"obj":"SO:0000704"},{"id":"T572","span":{"begin":651,"end":661},"obj":"CHEBI:26130"},{"id":"T573","span":{"begin":662,"end":669},"obj":"UBERON:0000966"},{"id":"T574","span":{"begin":786,"end":803},"obj":"CL:0000604"},{"id":"T575","span":{"begin":962,"end":966},"obj":"_FRAGMENT"},{"id":"T576","span":{"begin":974,"end":988},"obj":"CL:0000495"},{"id":"T577","span":{"begin":969,"end":988},"obj":"CL:0000573"},{"id":"T578","span":{"begin":992,"end":997},"obj":"CL:0000573"},{"id":"T579","span":{"begin":1059,"end":1065},"obj":"UBERON:0000966"},{"id":"T580","span":{"begin":1073,"end":1078},"obj":"NCBITaxon:9606"},{"id":"T581","span":{"begin":1111,"end":1118},"obj":"UBERON:0000966"},{"id":"T582","span":{"begin":1159,"end":1168},"obj":"PR:000001245"},{"id":"T583","span":{"begin":1217,"end":1229},"obj":"PR:000001195"},{"id":"T584","span":{"begin":1219,"end":1223},"obj":"CL:0000573"},{"id":"T585","span":{"begin":1230,"end":1240},"obj":"GO:0010467"},{"id":"T586","span":{"begin":1285,"end":1290},"obj":"CL:0000573"},{"id":"T587","span":{"begin":1552,"end":1559},"obj":"UBERON:0000966"},{"id":"T588","span":{"begin":1590,"end":1609},"obj":"UBERON:0001789"},{"id":"T589","span":{"begin":1596,"end":1603},"obj":"GO:0005634"},{"id":"T590","span":{"begin":1611,"end":1614},"obj":"UBERON:0001789"},{"id":"T591","span":{"begin":1622,"end":1635},"obj":"CL:0000210"},{"id":"T592","span":{"begin":1636,"end":1647},"obj":"GO:0044297"},{"id":"T593","span":{"begin":1667,"end":1674},"obj":"UBERON:0000966"},{"id":"T594","span":{"begin":1761,"end":1766},"obj":"NCBITaxon:10088"},{"id":"T595","span":{"begin":1767,"end":1775},"obj":"SO:0000855"},{"id":"T596","span":{"begin":1779,"end":1784},"obj":"PR:000011403"},{"id":"T597","span":{"begin":1832,"end":1839},"obj":"UBERON:0000966"},{"id":"T598","span":{"begin":1897,"end":1904},"obj":"UBERON:0000966"},{"id":"T599","span":{"begin":1949,"end":1952},"obj":"UBERON:0001789"},{"id":"T600","span":{"begin":2011,"end":2016},"obj":"NCBITaxon:10088"},{"id":"T601","span":{"begin":2038,"end":2053},"obj":"GO:1990603"},{"id":"T602","span":{"begin":2235,"end":2242},"obj":"PR:000001195"},{"id":"T603","span":{"begin":2269,"end":2275},"obj":"UBERON:0000966"},{"id":"T604","span":{"begin":2373,"end":2377},"obj":"CL:0000573"},{"id":"T605","span":{"begin":2378,"end":2383},"obj":"SO:0000704"},{"id":"T606","span":{"begin":2533,"end":2547},"obj":"CL:0000210"},{"id":"T607","span":{"begin":2566,"end":2571},"obj":"NCBITaxon:10088"},{"id":"T608","span":{"begin":2596,"end":2609},"obj":"GO:0097617"},{"id":"T609","span":{"begin":2663,"end":2670},"obj":"PR:000001195"},{"id":"T610","span":{"begin":2722,"end":2726},"obj":"CL:0000573"},{"id":"T611","span":{"begin":2736,"end":2741},"obj":"SO:0000704"},{"id":"T612","span":{"begin":2749,"end":2772},"obj":"CL:0000604"},{"id":"T613","span":{"begin":2833,"end":2840},"obj":"GO:0010467"},{"id":"T614","span":{"begin":2841,"end":2844},"obj":"CL:0000604"},{"id":"T615","span":{"begin":2849,"end":2853},"obj":"CL:0000573"},{"id":"T616","span":{"begin":2854,"end":2859},"obj":"SO:0000704"},{"id":"T617","span":{"begin":2871,"end":2877},"obj":"UBERON:0000966"},{"id":"T618","span":{"begin":2952,"end":2956},"obj":"CL:0000604"},{"id":"T619","span":{"begin":2961,"end":2966},"obj":"CL:0000573"}],"relations":[{"id":"R293","pred":"_lexicallyChainedTo","subj":"T576","obj":"T575"}],"text":"Introduction\nEnhanced S-cone syndrome (ESCS) is an unusual disease of photoreceptors that includes night blindness (suggestive of rod dysfunction), an abnormal electroretinogram (ERG) with a waveform that is nearly identical under both light and dark adaptation, and an increased sensitivity of the ERG to short-wavelength light [1,2]. The disease is caused by mutations in the orphan nuclear receptor transcription factor NR2E3 (also known as photoreceptor nuclear receptor), which is expressed exclusively in rods [3,4]. Recent human genetic studies have also demonstrated mutations in this gene in Goldmann-Favre syndrome and many cases of clumped pigmentary retinal degeneration [5].\nThe initial reports of patients with ESCS attributed the unusual ERG to an abnormally functioning rod photoreceptor system with persistent activity under light adaptation [6–8]. Subsequent studies, however, concluded that the ERG was due to supernumerary short-wavelength (“blue”) cone photoreceptors (S-cones) in these patients [1,2,9–11]. Histopathologic analysis of a retina from a human patient with ESCS and extensive retinal degeneration demonstrated an absence of rhodopsin-positive cells and an increase in the number of S-cone opsin-expressing cells. Nevertheless, the overall density of cones was only modestly increased in this patient (approximately 2-fold), suggesting that there might be additional factors that contribute to the very large, light-adapted ERG seen in this disease. In addition to the ERG findings, patients with ESCS have dysmorphic retinas with rosette formation in the outer nuclear layer (ONL) where photoreceptor cell bodies reside, and a slow retinal degeneration that can ultimately lead to complete blindness [12–14].\nMutations in the mouse ortholog of NR2E3 have been identified in the spontaneous mutant retinal degeneration 7 (rd7) [15]. This mutant demonstrates slow retinal degeneration and abnormal lamination of the ONL with rosette formation [15,16]. Curiously, the ERG of the mouse under both light and dark adaptation has been reported to be normal, showing progressive attenuation with time, presumably due to degenerative cell loss [15]. A prior study showed a 2- to 3-fold increase in the number S-opsin–positive cells in the rd7 retina compared to wild type [17]. In addition, two groups recently reported derepression of additional cone genes in the rd7 mutant [18,19].\nIn order to better understand the mechanistic basis of ESCS, we undertook a molecular and ultrastructural analysis of the photoreceptors of the rd7 mutant mouse. Microarray and in situ hybridization analyses revealed a modest increase in the number of S-opsin–positive cells and widespread derepression of many cone-specific genes within rod photoreceptor cells. Ultrastructural studies demonstrated that the cells that coexpress rod and cone genes in the rd7 retina represent a morphologically hybrid cell type, intermediate between normal rods and cones."}

{"project":"2_test","denotations":[{"id":"16110338-2335450-85798498","span":{"begin":330,"end":331},"obj":"2335450"},{"id":"16110338-7645276-85798499","span":{"begin":332,"end":333},"obj":"7645276"},{"id":"16110338-10655056-85798500","span":{"begin":517,"end":518},"obj":"10655056"},{"id":"16110338-15277507-85798501","span":{"begin":519,"end":520},"obj":"15277507"},{"id":"16110338-12963616-85798502","span":{"begin":684,"end":685},"obj":"12963616"},{"id":"16110338-2787013-85798503","span":{"begin":860,"end":861},"obj":"2787013"},{"id":"16110338-2789128-85798503","span":{"begin":860,"end":861},"obj":"2789128"},{"id":"16110338-2335450-85798504","span":{"begin":1018,"end":1019},"obj":"2335450"},{"id":"16110338-7645276-85798505","span":{"begin":1020,"end":1021},"obj":"7645276"},{"id":"16110338-2012146-85798506","span":{"begin":1022,"end":1023},"obj":"2012146"},{"id":"16110338-2378376-85798506","span":{"begin":1022,"end":1023},"obj":"2378376"},{"id":"16110338-1743268-85798506","span":{"begin":1022,"end":1023},"obj":"1743268"},{"id":"16110338-15229190-85798507","span":{"begin":1736,"end":1738},"obj":"15229190"},{"id":"16110338-11773633-85798507","span":{"begin":1736,"end":1738},"obj":"11773633"},{"id":"16110338-301373-85798507","span":{"begin":1736,"end":1738},"obj":"301373"},{"id":"16110338-10805811-85798508","span":{"begin":1862,"end":1864},"obj":"10805811"},{"id":"16110338-10805811-85798509","span":{"begin":1977,"end":1979},"obj":"10805811"},{"id":"16110338-12407160-85798510","span":{"begin":1980,"end":1982},"obj":"12407160"},{"id":"16110338-10805811-85798511","span":{"begin":2171,"end":2173},"obj":"10805811"},{"id":"16110338-11487564-85798512","span":{"begin":2299,"end":2301},"obj":"11487564"},{"id":"16110338-15634773-85798513","span":{"begin":2403,"end":2405},"obj":"15634773"},{"id":"16110338-15689355-85798514","span":{"begin":2406,"end":2408},"obj":"15689355"},{"id":"T34232","span":{"begin":330,"end":331},"obj":"2335450"},{"id":"T59131","span":{"begin":332,"end":333},"obj":"7645276"},{"id":"T82344","span":{"begin":517,"end":518},"obj":"10655056"},{"id":"T22466","span":{"begin":519,"end":520},"obj":"15277507"},{"id":"T58203","span":{"begin":684,"end":685},"obj":"12963616"},{"id":"T14338","span":{"begin":860,"end":861},"obj":"2787013"},{"id":"T26432","span":{"begin":860,"end":861},"obj":"2789128"},{"id":"T77085","span":{"begin":1018,"end":1019},"obj":"2335450"},{"id":"T40817","span":{"begin":1020,"end":1021},"obj":"7645276"},{"id":"T88637","span":{"begin":1022,"end":1023},"obj":"2012146"},{"id":"T68689","span":{"begin":1022,"end":1023},"obj":"2378376"},{"id":"T15477","span":{"begin":1022,"end":1023},"obj":"1743268"},{"id":"T72997","span":{"begin":1736,"end":1738},"obj":"15229190"},{"id":"T6341","span":{"begin":1736,"end":1738},"obj":"11773633"},{"id":"T19811","span":{"begin":1736,"end":1738},"obj":"301373"},{"id":"T9696","span":{"begin":1862,"end":1864},"obj":"10805811"},{"id":"T89145","span":{"begin":1977,"end":1979},"obj":"10805811"},{"id":"T79486","span":{"begin":1980,"end":1982},"obj":"12407160"},{"id":"T51616","span":{"begin":2171,"end":2173},"obj":"10805811"},{"id":"T88805","span":{"begin":2299,"end":2301},"obj":"11487564"},{"id":"T72364","span":{"begin":2403,"end":2405},"obj":"15634773"},{"id":"T45111","span":{"begin":2406,"end":2408},"obj":"15689355"}],"text":"Introduction\nEnhanced S-cone syndrome (ESCS) is an unusual disease of photoreceptors that includes night blindness (suggestive of rod dysfunction), an abnormal electroretinogram (ERG) with a waveform that is nearly identical under both light and dark adaptation, and an increased sensitivity of the ERG to short-wavelength light [1,2]. The disease is caused by mutations in the orphan nuclear receptor transcription factor NR2E3 (also known as photoreceptor nuclear receptor), which is expressed exclusively in rods [3,4]. Recent human genetic studies have also demonstrated mutations in this gene in Goldmann-Favre syndrome and many cases of clumped pigmentary retinal degeneration [5].\nThe initial reports of patients with ESCS attributed the unusual ERG to an abnormally functioning rod photoreceptor system with persistent activity under light adaptation [6–8]. Subsequent studies, however, concluded that the ERG was due to supernumerary short-wavelength (“blue”) cone photoreceptors (S-cones) in these patients [1,2,9–11]. Histopathologic analysis of a retina from a human patient with ESCS and extensive retinal degeneration demonstrated an absence of rhodopsin-positive cells and an increase in the number of S-cone opsin-expressing cells. Nevertheless, the overall density of cones was only modestly increased in this patient (approximately 2-fold), suggesting that there might be additional factors that contribute to the very large, light-adapted ERG seen in this disease. In addition to the ERG findings, patients with ESCS have dysmorphic retinas with rosette formation in the outer nuclear layer (ONL) where photoreceptor cell bodies reside, and a slow retinal degeneration that can ultimately lead to complete blindness [12–14].\nMutations in the mouse ortholog of NR2E3 have been identified in the spontaneous mutant retinal degeneration 7 (rd7) [15]. This mutant demonstrates slow retinal degeneration and abnormal lamination of the ONL with rosette formation [15,16]. Curiously, the ERG of the mouse under both light and dark adaptation has been reported to be normal, showing progressive attenuation with time, presumably due to degenerative cell loss [15]. A prior study showed a 2- to 3-fold increase in the number S-opsin–positive cells in the rd7 retina compared to wild type [17]. In addition, two groups recently reported derepression of additional cone genes in the rd7 mutant [18,19].\nIn order to better understand the mechanistic basis of ESCS, we undertook a molecular and ultrastructural analysis of the photoreceptors of the rd7 mutant mouse. Microarray and in situ hybridization analyses revealed a modest increase in the number of S-opsin–positive cells and widespread derepression of many cone-specific genes within rod photoreceptor cells. Ultrastructural studies demonstrated that the cells that coexpress rod and cone genes in the rd7 retina represent a morphologically hybrid cell type, intermediate between normal rods and cones."}