{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:32:48Z","timestamp":1792157568682,"version":"4.4.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"6","funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Save sight society NZ, Retina NZ, and the Ombler trust"},{"name":"National Institute of Health Research Biomedical Research Centre"},{"DOI":"10.13039\/501100012617","name":"Moorfields Eye Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012617","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCL Institute of Ophthalmology"},{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Great Ormond Street Hospital Institute for Child Health"},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear.<\/jats:p>\n                  <jats:p>We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists.<\/jats:p>\n                  <jats:p>Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.<\/jats:p>","DOI":"10.1093\/brain\/awae055","type":"journal-article","created":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T20:01:36Z","timestamp":1715544096000},"page":"2085-2097","source":"Crossref","is-referenced-by-count":15,"title":["Neuropathy target esterase activity defines phenotypes among\n                    <i>PNPLA6<\/i>\n                    disorders"],"prefix":"10.1093","volume":"147","author":[{"given":"James","family":"Liu","sequence":"first","affiliation":[{"name":"Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"He","sequence":"additional","affiliation":[{"name":"Fermentation Facility, Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute , Bethesda, MD 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V","family":"Sergeev","sequence":"additional","affiliation":[{"name":"Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1114-4697","authenticated-orcid":false,"given":"Haohua","family":"Qian","sequence":"additional","affiliation":[{"name":"Visual Function Core, National Eye Institute, National Institutes of Health , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Visual Function Core, National Eye Institute, National Institutes of Health , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijin","family":"Dong","sequence":"additional","affiliation":[{"name":"Genetic Engineering Core, National Eye Institute, National Institutes of Health , Bethesda, MD 20892 , 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