{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:52:00Z","timestamp":1768506720742,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,11]]},"group-title":"Neuroscience","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Biallelic pathogenic variants in the\n                  <jats:italic>PNPLA6<\/jats:italic>\n                  gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies.\n                  <jats:italic>PNPLA6<\/jats:italic>\n                  encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with\n                  <jats:italic>PNPLA6<\/jats:italic>\n                  variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across\n                  <jats:italic>PNPLA6<\/jats:italic>\n                  -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying\n                  <jats:italic>PNPLA6<\/jats:italic>\n                  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. Thus,\n                  <jats:italic>PNPLA6<\/jats:italic>\n                  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.\n                <\/jats:p>","DOI":"10.1101\/2023.06.09.544373","type":"posted-content","created":{"date-parts":[[2023,6,11]],"date-time":"2023-06-11T23:35:10Z","timestamp":1686526510000},"source":"Crossref","is-referenced-by-count":1,"title":["Neuropathy target esterase activity predicts retinopathy among\n                  <i>PNPLA6<\/i>\n                  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