{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:04:46Z","timestamp":1788365086345,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Istituto Superiore di Sanit\u00e0","award":["ISS20-5656c541c257"],"award-info":[{"award-number":["ISS20-5656c541c257"]}]},{"name":"Istituto Superiore di Sanit\u00e0","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}]},{"name":"Italian Ministry of Health","award":["ISS20-5656c541c257"],"award-info":[{"award-number":["ISS20-5656c541c257"]}]},{"name":"Italian Ministry of Health","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>O-mannosylation is a post-translational modification required for the proper function of various proteins and critical for development and growth. POMGNT1 encodes the enzyme O-linked-mannose \u03b2-1,2-N-acetylglucosaminyltransferase 1, which catalyzes the second step in the synthesis of \u03b1-dystroglycan O-mannosyl glycans. Among POMGNT1-related \u03b1-dystroglycanopathies, muscle\u2013eye\u2013brain (MEB) disease presents with congenital muscular dystrophy, structural brain abnormalities, and retinal dystrophy. Defects in protein O-mannosylation due to biallelic loss-of-function POMGNT1 mutations produce disturbances in assembling and organizing the basal membrane in the neuroretinal system, involving both the central and peripheral nervous systems. In the retina, POMGNT1 is expressed in photoreceptors and is localized near the photoreceptor cilium basal body, a structure critical for protein transport. Recent studies have reported an isolated degenerative ocular phenotype without any involvement of muscular or neuronal tissues. Here, we report on a family with three siblings affected by an apparently isolated clinically variable retinal disease and sharing biallelic inactivating POMGNT1 variants. Notably, the rod-cone dystrophy phenotype in the three siblings varied significantly in onset, presentation, and severity. These findings provide further evidence of the clinical variability associated with defective POMGNT1 function.<\/jats:p>","DOI":"10.3390\/ijms26073278","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T04:06:05Z","timestamp":1743566765000},"page":"3278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Variable Ophthalmologic Phenotypes Associated with Biallelic Loss-of-Function Variants in POMGNT1"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-1243","authenticated-orcid":false,"given":"Lucia","family":"Ziccardi","sequence":"first","affiliation":[{"name":"Clinical and Research Center of Neurophthalmology and Genetic and Rare Diseases of the Eye, IRCCS-Fondazione Bietti, 00198 Rome, Italy"},{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucilla","family":"Barbano","sequence":"additional","affiliation":[{"name":"Clinical and Research Center of Neurophthalmology and Genetic and Rare Diseases of the Eye, IRCCS-Fondazione Bietti, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-3964","authenticated-orcid":false,"given":"Mattia","family":"D\u2019Andrea","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1556-4998","authenticated-orcid":false,"given":"Alessandro","family":"Bruselles","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4395-0818","authenticated-orcid":false,"given":"Carmen","family":"Dell\u2019Aquila","sequence":"additional","affiliation":[{"name":"Clinical and Research Center of Neurophthalmology and Genetic and Rare Diseases of the Eye, IRCCS-Fondazione Bietti, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-7753","authenticated-orcid":false,"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Mancini","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Leone","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"},{"name":"Department of Humanities, Law and Economics, Telematic University Leonardo da Vinci, UNIDAV, 66010 Torrevecchia Teatina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4584-0663","authenticated-orcid":false,"given":"Mattia","family":"Carvetta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Biochemical Sciences \u201cAlessandro Rossi Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-2017","authenticated-orcid":false,"given":"Maria","family":"Albanese","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0415-3285","authenticated-orcid":false,"given":"Emilia","family":"Stellacci","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Cordeddu","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"ref_1","first-page":"658","article-title":"Expression pattern in retinal photoreceptors of POMGnT1, a protein involved in muscle-eye-brain disease","volume":"22","author":"Uribe","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1093\/glycob\/cwx062","article-title":"Recent advancements in understanding mammalian O-mannosylation","volume":"27","author":"Sheikh","year":"2017","journal-title":"Glycobiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e14473","DOI":"10.7554\/eLife.14473","article-title":"The functional O-mannose glycan on \u03b1-dystroglycan contains a phospho-ribitol primed for matriglycan addition","volume":"5","author":"Praissman","year":"2016","journal-title":"eLife"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bbrc.2004.05.129","article-title":"Structure\u2013function analysis of human protein O-linked mannose \u03b21,2-N-acetylglucosaminyltransferase 1, POMGnT1","volume":"320","author":"Manya","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fu, X., Yang, H., Jiao, H., Wang, S., Liu, A., Li, X., Xiao, J., Yang, Y., Wu, X., and Xiong, H. (2017). Novel copy number variation of POMGNT1 associated with muscle-eye-brain disease detected by next-generation sequencing. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-07349-8"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1093\/hmg\/ddw022","article-title":"in POMGNT1 cause non-syndromic retinitis pigmentosa","volume":"25","author":"Xu","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1167\/iovs.16-19463","article-title":"Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa","volume":"57","author":"Wang","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Patel, A., Cui, R., Odom, J.V., and Leys, M. (2023). Case Series on Autosomal Recessive Non-Syndromic Retinitis Pigmentosa Caused by POMGNT1 Mutations with a Report of a New Variant. J. Clin. Med., 12.","DOI":"10.3390\/jcm12247549"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nguyen, X.T., Moekotte, L., Plomp, A.S., Bergen, A.A., van Genderen, M.M., and Boon, C.J.F. (2023). Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087481"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1001\/archneurol.2007.2","article-title":"Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant","volume":"65","author":"Clement","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1093\/hmg\/10.25.2851","article-title":"Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C","volume":"10","author":"Brockington","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S0002-9440(10)63160-4","article-title":"Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies","volume":"164","author":"Brown","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ejpn.2007.06.008","article-title":"Severe muscle-eye-brain disease is associated with a homozygous mutation in the POMGnT1 gene","volume":"12","author":"Teber","year":"2008","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1093\/brain\/awm212","article-title":"Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan","volume":"130","author":"Godfrey","year":"2007","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"a041652","DOI":"10.1101\/cshperspect.a041652","article-title":"The Extraordinary Phenotypic and Genetic Variability of Retinal and Macular Degenerations: The Relevance to Therapeutic Developments","volume":"14","author":"Audo","year":"2024","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10633-011-9296-8","article-title":"International Society For Clinical Electrophysiology of Vision. ISCEV standard for clinical multifocal electroretinography (mfERG)","volume":"124","author":"Hood","year":"2012","journal-title":"Doc. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ajhg.2020.11.015","article-title":"SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling","volume":"108","author":"Lin","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ajhg.2020.06.018","article-title":"Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum","volume":"107","author":"Motta","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","first-page":"11.10.1","article-title":"From FastQ Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline","volume":"43","author":"Carneiro","year":"2013","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2013Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E2393","DOI":"10.1002\/humu.22376","article-title":"dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations","volume":"34","author":"Liu","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9280","DOI":"10.1073\/pnas.1525545113","article-title":"Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of \u03b1-dystroglycan","volume":"113","author":"Kuwabara","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3278\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:07:58Z","timestamp":1760029678000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3278"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":27,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073278"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073278","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,1]]}}}