{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:09:54Z","timestamp":1791346194818,"version":"4.3.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","award":["11220200102210"],"award-info":[{"award-number":["11220200102210"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Secretar\u00eda de Ciencia y Tecnolog\u00eda, Universidad Nacional de C\u00f3rdoba","award":["33620180100675CB"],"award-info":[{"award-number":["33620180100675CB"]}]},{"name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica\u2014Ministerio de Ciencia y Tecnolog\u00eda","award":["0950-2020-2024"],"award-info":[{"award-number":["0950-2020-2024"]}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT-2019-1772"],"award-info":[{"award-number":["PICT-2019-1772"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT-2021-0409"],"award-info":[{"award-number":["PICT-2021-0409"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>CLN7 is a lysosomal storage disease caused by pathogenic variants in the MFSD8\/CLN7 gene. Typically neurodegenerative, patients present seizures and developmental delay since 2\u20136\u00a0years of age and a rapid psychomotor, verbal, and visual deterioration that leads to premature death. However, \u2018atypical\u2019 cases have also been reported. Although more than 80 DNA variants in the MFSD8\/CLN7 gene have been reported, no data about a genotype\/phenotype correlation is available. Here, we analyze five \u2018classical\u2019 and \u2018atypical\u2019 CLN7 patients by molecular and computational methods. Four variants have been found: c.103C\u2009&amp;gt;\u2009T (p.Arg35*, pathogenic), c.1394G\u2009&amp;gt;\u2009A (p.Arg465Gln, pathogenic), c.863\u2009+\u20091G\u2009&amp;gt;\u2009A (likely pathogenic), and c.863\u2009+\u20094A\u2009&amp;gt;\u2009G (of uncertain significance). Both splice variants showed altering of the splicing process on a minigene reporter assay. Furthermore, exon 8 was deleted in the MFSD8\/CLN7 cDNA of blood samples from two patients carrying the splicing variants, demonstrating their effect. The c.863\u2009+\u20094A\u2009&amp;gt;\u2009G variant also showed a residual wildtype MFSD8\/CLN7 expression and, thus, explaining the milder phenotype. Finally, a clustered geographical distribution of the c.103C\u2009&amp;gt;\u2009T and c.863\u2009+\u20094A\u2009&amp;gt;\u2009G variants was observed in the northeast and center of Argentina, respectively. Our data confirm the pathogenicity of the c.863\u2009+\u20091G\u2009&amp;gt;\u2009A variant and reclassify the c.863\u2009+\u20094A\u2009&amp;gt;\u2009G variant as pathogenic by adding experimental data, offering new information for a precise prognosis, and expanding the genetic and epidemiological spectrum of CLN7 in the South American region. Ultimately, we seek to raise awareness about the existence of this pathology in the region to reduce the so-called \u2018diagnostic odyssey\u2019 in pediatric patients.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf067","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T21:29:10Z","timestamp":1746566950000},"page":"1157-1167","source":"Crossref","is-referenced-by-count":4,"title":["UNRAVELING CLN7 disease: the distinct roles of two close <i>MFSD8\/CLN7<\/i> splice variants in phenotypic expression"],"prefix":"10.1093","volume":"34","author":[{"given":"Ana Clara","family":"Venier","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones en Ciencias de la Salud - Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (INICSA - CONICET) , Boulevard de la Reforma y Enfermera Gordillo, X5016, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Centro de Microscop\u00eda Electr\u00f3nica, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de C\u00f3rdoba , Boulevard de la Reforma y Enfermera Gordillo, X5016, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Programa de Investigaci\u00f3n Translacional de Lipofuscinosis Ceroidea Neuronal, Hospital de Ni\u00f1os de la Sant\u00edsima Trinidad , Ferroviarios 1250, X5014, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sof\u00eda","family":"Savy","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, Medina Allende s\/n, X5000, C\u00f3rdoba, Argentina"},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda - Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI - CONICET) , Medina Allende s\/n, X5000, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Carro","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, Medina Allende s\/n, X5000, C\u00f3rdoba, Argentina"},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda - Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI - CONICET) , Medina Allende s\/n, X5000, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Guelbert","sequence":"additional","affiliation":[{"name":"Programa de Investigaci\u00f3n Translacional de Lipofuscinosis Ceroidea Neuronal, Hospital de Ni\u00f1os de la Sant\u00edsima Trinidad , Ferroviarios 1250, X5014, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Servicio de Enfermedades Metab\u00f3licas Hereditarias, Hospital de Ni\u00f1os de la Sant\u00edsima Trinidad , Ferroviarios 1250, X5014, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezequiel","family":"Grondona","sequence":"additional","affiliation":[{"name":"Centro de Microscop\u00eda Electr\u00f3nica, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de C\u00f3rdoba , Boulevard de la Reforma y Enfermera Gordillo, X5016, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norberto","family":"Guelbert","sequence":"additional","affiliation":[{"name":"Programa de Investigaci\u00f3n Translacional de Lipofuscinosis Ceroidea Neuronal, Hospital de Ni\u00f1os de la Sant\u00edsima Trinidad , Ferroviarios 1250, X5014, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Servicio de Enfermedades Metab\u00f3licas Hereditarias, Cl\u00ednica Universitaria \u201cReina Fabiola\u201d, Universidad Cat\u00f3lica de C\u00f3rdoba , Oncativo 1248, X5004, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Nicola","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, Medina Allende s\/n, X5000, C\u00f3rdoba, Argentina"},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda - Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI - CONICET) , Medina Allende s\/n, X5000, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Favio","family":"Pesaola","sequence":"additional","affiliation":[{"name":"Programa de Investigaci\u00f3n Translacional de Lipofuscinosis Ceroidea Neuronal, Hospital de Ni\u00f1os de la Sant\u00edsima Trinidad , Ferroviarios 1250, X5014, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Department of Pediatrics, Washington University in Saint Louis School of Medicine , 660 S Euclid Ave, Saint Louis, 63110, MO ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Luc\u00eda","family":"De Paul","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones en Ciencias de la Salud - Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (INICSA - CONICET) , Boulevard de la Reforma y Enfermera Gordillo, X5016, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Centro de Microscop\u00eda Electr\u00f3nica, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de C\u00f3rdoba , Boulevard de la Reforma y Enfermera Gordillo, X5016, C\u00f3rdoba ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"2025062620245653900_ref1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fneur.2022.811686","article-title":"Neuronal ceroid Lipofuscinosis: the multifaceted approach to the clinical issues, an overview","volume":"13","author":"Simonati","year":"2022","journal-title":"Front Neurol"},{"key":"2025062620245653900_ref2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jnen\/62.1.1","article-title":"The neuronal ceroid-lipofuscinoses","volume":"62","author":"Haltia","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025062620245653900_ref3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41572-018-0025-4","article-title":"Lysosomal sotorage diseases","volume":"4","author":"Platt","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"2025062620245653900_ref4","doi-asserted-by":"crossref","first-page":"165570","DOI":"10.1016\/j.bbadis.2019.165570","article-title":"Pathomechanisms in the neuronal ceroid lipofuscinoses","volume":"1866","author":"Nelvagal","year":"2020","journal-title":"Biochim Biophys Acta Mol basis Dis"},{"key":"2025062620245653900_ref5","doi-asserted-by":"crossref","first-page":"754045","DOI":"10.3389\/fneur.2021.754045","article-title":"The genetic basis of phenotypic heterogeneity in the neuronal ceroid Lipofuscinoses","volume":"12","author":"Gardner","year":"2021","journal-title":"Front Neurol"},{"key":"2025062620245653900_ref6","doi-asserted-by":"crossref","first-page":"165571","DOI":"10.1016\/j.bbadis.2019.165571","article-title":"Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses","volume":"1866","author":"Butz","year":"2020","journal-title":"Biochim Biophys Acta Mol basis Dis"},{"key":"2025062620245653900_ref7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13024-018-0300-6","article-title":"Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses","volume":"14","author":"Mukherjee","year":"2019","journal-title":"Mol Neurodegener"},{"key":"2025062620245653900_ref8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1006\/mgme.1999.2804","article-title":"A new locus for variant late infantile neuronal ceroid lipofuscinosis - CLN7","volume":"66","author":"Wheeler","year":"1999","journal-title":"Mol Genet Metab"},{"key":"2025062620245653900_ref9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1086\/518902","article-title":"The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter","volume":"81","author":"Siintola","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2025062620245653900_ref10","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1093\/brain\/awn366","article-title":"Mutations in CLN7\/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis","volume":"132","author":"Kousi","year":"2009","journal-title":"Brain"},{"key":"2025062620245653900_ref11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10048-008-0153-1","article-title":"A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis","volume":"10","author":"Stogmann","year":"2009","journal-title":"Neurogenetics"},{"key":"2025062620245653900_ref12","first-page":"395","article-title":"Clinical characteristics and genetic analysis of a case with adult neuronal ceroid lipofuscinosis type 7 due to variant of MFSD8 gene","volume":"40","author":"He","year":"2023","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"2025062620245653900_ref13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/humu.21624","article-title":"Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses","volume":"33","author":"Kousi","year":"2012","journal-title":"Hum Mutat"},{"key":"2025062620245653900_ref14","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1097\/ICB.0000000000001553","article-title":"Multimodal imaging of a novel MFSD8\/CLN7 mutation associated with non-syndromic symmetric adult-onset macular dystrophy","volume":"19","author":"Gelormini","year":"2024","journal-title":"Retin Cases Brief Rep"},{"key":"2025062620245653900_ref15","doi-asserted-by":"crossref","first-page":"715100","DOI":"10.3389\/fgene.2021.715100","article-title":"Simultaneous identification of both MFSD8 and RDH12 pathogenic variants in a Chinese family affected with retinitis Pigmentosa","volume":"12","author":"Wang","year":"2021","journal-title":"Front Genet"},{"key":"2025062620245653900_ref16","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ophtha.2014.07.040","article-title":"Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy","volume":"122","author":"Roosing","year":"2015","journal-title":"Ophthalmology"},{"key":"2025062620245653900_ref17","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/cge.13673","article-title":"Functional characterization of novel MFSD8 pathogenic variants anticipates neurological involvement in juvenile isolated maculopathy","volume":"97","author":"Bauwens","year":"2020","journal-title":"Clin Genet"},{"key":"2025062620245653900_ref18","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1167\/iovs.16-20608","article-title":"Specific alleles of CLN7\/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a Spectrum of nonsyndromic retinal dystrophy","volume":"58","author":"Khan","year":"2017","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2025062620245653900_ref19","doi-asserted-by":"crossref","first-page":"e0207958","DOI":"10.1371\/journal.pone.0207958","article-title":"Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa","volume":"13","author":"Birtel","year":"2018","journal-title":"PLoS One"},{"key":"2025062620245653900_ref20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1080\/13816810.2019.1592200","article-title":"MFSD8 gene mutations; evidence for phenotypic heterogeneity","volume":"40","author":"Zare-Abdollahi","year":"2019","journal-title":"Ophthalmic Genet"},{"key":"2025062620245653900_ref21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1167\/iovs.64.3.23","article-title":"Phenotypic variability of retinal disease among a cohort of patients with variants in the CLN genes","volume":"64","author":"Kolesnikova","year":"2023","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2025062620245653900_ref22","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1080\/13816810.2022.2092758","article-title":"Novel MFSD8 mutation causing non-syndromic asymmetric adult-onset macular dystrophy","volume":"44","author":"Priluck","year":"2023","journal-title":"Ophthalmic Genet"},{"key":"2025062620245653900_ref23","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1016\/j.ophtha.2017.04.008","article-title":"Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease","volume":"124","author":"Stone","year":"2017","journal-title":"Ophthalmology"},{"key":"2025062620245653900_ref24","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.3390\/ijms23084294","article-title":"Contribution of whole-genome sequencing and transcript analysis to decipher retinal diseases associated with MFSD8 variants","volume":"23","author":"Poncet","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025062620245653900_ref25","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1080\/13816810.2023.2183224","article-title":"A novel ocular phenotype associated with pathogenic variants in MFSD8 leading to macular dystrophy","volume":"44","author":"Beckman","year":"2023","journal-title":"Ophthalmic Genet"},{"key":"2025062620245653900_ref26","doi-asserted-by":"crossref","first-page":"e2505","DOI":"10.1002\/mgg3.2505","article-title":"Maculopathy and adult-onset ataxia in patients with biallelic MFSD8 variants","volume":"12","author":"Dobloug","year":"2024","journal-title":"Mol Genet Genomic Med"},{"key":"2025062620245653900_ref27","doi-asserted-by":"crossref","first-page":"eabj9608","DOI":"10.1126\/sciadv.abj9608","article-title":"CLN7 is an organellar chloride channel regulating lysosomal function","volume":"7","author":"Wang","year":"2021","journal-title":"Sci Adv"},{"key":"2025062620245653900_ref28","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.1093\/hmg\/ddq381","article-title":"Expression and lysosomal targeting of CLN7, a major facilitator superfamily transporter associated with variant late-infantile neuronal ceroid lipofuscinosis","volume":"19","author":"Sharifi","year":"2010","journal-title":"Hum Mol Genet"},{"key":"2025062620245653900_ref29","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/humu.20975","article-title":"Mutations in MFSD8\/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis","volume":"30","author":"Aiello","year":"2009","journal-title":"Hum Mutat"},{"key":"2025062620245653900_ref30","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s00439-017-1821-8","article-title":"The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes","volume":"136","author":"Monies","year":"2017","journal-title":"Hum Genet"},{"key":"2025062620245653900_ref31","first-page":"20","article-title":"High diagnostic yield of direct sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses","volume":"50","author":"Jilani","year":"2019","journal-title":"JIMD 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MFSD8","volume":"14","author":"Pasquetti","year":"2023","journal-title":"Genes (Basel)"},{"key":"2025062620245653900_ref38","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1111\/j.1600-0854.2010.01073.x","article-title":"Lysosomal targeting of the CLN7 membrane glycoprotein and transport via the plasma membrane require a dileucine motif","volume":"11","author":"Steenhuis","year":"2010","journal-title":"Traffic"},{"key":"2025062620245653900_ref39","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1016\/j.bbadis.2015.05.003","article-title":"The neuronal ceroid lipofuscinoses program: a translational research experience in Argentina","volume":"1852","author":"Kohan","year":"2015","journal-title":"Biochim Biophys Acta Mol basis Dis"},{"key":"2025062620245653900_ref40","doi-asserted-by":"crossref","first-page":"920421","DOI":"10.3389\/fneur.2022.920421","article-title":"Neuronal ceroid lipofuscinosis in the south American-Caribbean region: an epidemiological 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