Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course
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http://creativecommons.org/licenses/by/4.0/Type
ArticleAuthors
Maroofian, RezaGubas, Andrea
Kaiyrzhanov, Rauan
Scala, Marcello
Hundallah, Khalid
Severino, Mariasavina
Abdel-Hamid, Mohamed S
Rosenfeld, Jill A
Ebrahimi-Fakhari, Darius
Ali, Zahir
Rahim, Fazal
Houlden, Henry
Tooze, Sharon A
Alsaleh, Norah S
Zaki, Maha S
KAUST Department
Biological and Environmental Science and Engineering (BESE) DivisionOnline Publication Date
2021-09-03Print Publication Date
2021-07-01Date
2021-09-03Submitted Date
2021-03-17Abstract
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 harboring 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.Citation
Maroofian, R., Gubas, A., Kaiyrzhanov, R., Scala, M., Hundallah, K., Severino, M., … Zaki, M. S. (2021). Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course. Brain Communications. doi:10.1093/braincomms/fcab183Acknowledgements
The authors would like to thank the patients and their families for their support of this study. This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.This research was funded in part, by the Wellcome Trust [WT093205MA, WT104033AIA and the Synaptopathies Strategic Award, 165908]. The work at University of Maryland, Baltimore, USA was supported by National Institute of Neurological Disorders and Stroke (NINDS) (R01NS107428) (to S.R.). This study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research United Kingdom, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy United Kingdom (MDUK), Muscular Dystrophy Association (MDA USA). SAT was supported by the Francis Crick Institute which receives its core funding from Cancer Research United Kingdom (FC001187), the United Kingdom Medical Research Council (FC001187), and the Wellcome Trust (FC001187). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.