Liu, James;
He, Yi;
Lwin, Cara;
Han, Marina;
Guan, Bin;
Naik, Amelia;
Bender, Chelsea;
... Hufnagel, Robert B; + view all
(2024)
Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.
Brain
10.1093/brain/awae055.
(In press).
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Michaelides_Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders_AAM.pdf - Accepted Version Access restricted to UCL open access staff until 14 May 2025. Download (12MB) |
Abstract
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. 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. 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.
| Type: | Article |
|---|---|
| Title: | Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders |
| Location: | England |
| DOI: | 10.1093/brain/awae055 |
| Publisher version: | http://dx.doi.org/10.1093/brain/awae055 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | Boucher-Neuhäuser syndrome, Gordon-Holmes syndrome, Laurence-Moon syndrome, neurodegeneration, Oliver-McFarlane syndrome, spastic paraplegia type 39 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10193037 |
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