Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course
| العنوان: | Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course |
|---|---|
| المؤلفون: | Jill A. Rosenfeld, Marcello Scala, Rauan Kaiyrzhanov, Khalid Hundallah, Fazal Rahim, Andrea Gubas, Sharon A. Tooze, Zahir Ali, Mohamed Abdelhamid, Norah S Alsaleh, Darius Ebrahimi-Fakhari, Reza Maroofian, Mariasavina Severino, Henry Houlden, Maha S. Zaki |
| المصدر: | Brain Communications |
| بيانات النشر: | Oxford University Press, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Proband, Model organisms, congenital disorders of autophagy, Microcephaly, autophagy, WIPI2, Bioinformatics, Biochemistry & Proteomics, Imaging, Signalling & Oncogenes, Neurodevelopmental disorder, Intellectual disability, medicine, Missense mutation, Global developmental delay, Exome sequencing, Chemical Biology & High Throughput, business.industry, AcademicSubjects/SCI01870, General Engineering, Cell Biology, medicine.disease, neurodevelopmental disorder, Editor's Choice, WIPI2b, Original Article, AcademicSubjects/MED00310, business, Congenital disorder |
| الوصف: | WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here, two novel homozygous WIPI2 variants [c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)] were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harbouring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy. Maroofian et al. reported two novel homozygous WIPI2 variants [c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)] in four individuals of two consanguineous families with neurodevelopmental disorder and brain abnormalities. Expression of the Val184Gly mutant in WIPI2-knockout HEK293A cells resulted in a deficient LC3 lipidation rescue whereas Arg242Trp mutant increased LC3 lipidation. Graphical Abstract Graphical Abstract |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2632-1297 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::04cc1247431c38f63282c4f9b2d97a39Test http://europepmc.org/articles/PMC8453401Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....04cc1247431c38f63282c4f9b2d97a39 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26321297 |
|---|