A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities

Abstract

Defects in autophagy are implicated in a growing number of diseases. Jelani et al. identify a mutation in WIPI2 , a major autophagy gene, associated with a multisystemic global developmental disorder. Functional studies in cell lines derived from patients reveal significant reductions in the classic hallmarks of autophagy.

Autophagosome biogenesis and human health

“…LCLs from patients with the ATG5 E122D mutation showed a decrease in LC3 lipidation and autophagic flux but still retained a detectable level of flux 95 . This finding was also observed for those with the WIPI2 V249M mutation 53 . Among INPP5E knockout cell lines complemented by the transgenes with some mutations found in patients with Joubert syndrome, some of mild symptoms showed a slight but significant recovery in autophagic activity, but the severe symptoms did not show any recovery, showing a correlation between the enzymatic activity and the severity of symptoms 82 .…”

“…Consistent with this idea, mutations in the WIPI4 (WDR45) gene cause static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), a human genetic disease involving neurodegeneration 52 . WIPI2 gene is also known to be responsible for a hereditary disease showing neurological disorders (described below) 53 . FYVE domain-containing protein DFCP1 is often used as a marker of isolation membranes but is not functionally involved in autophagy itself 16,54 .…”

“…Since a loss of WIPI2 results in a defect in LC3 lipidation and the associated autophagosome formation, WIPI2 may have a distinct function in autophagy among human Atg18 paralogs 54 . Recently, individuals with a homozygous mutation in WIPI2 were reported to show developmental abnormalities and mental retardation 53 . Exome sequencing of two affected individuals identified the G745A mutation in exon 9 of the WIPI2 gene, which leads to a V249M amino acid change in the gene product.…”

“…Cerebellar dysfunction is suggested, as fine/gross motor activities are delayed in patients. Cardiac abnormalities shown by electrocardiograms were observed 53 . The clinical features were similar at some degree in the patients with the WIPI2 mutation and those with SENDA although the patient with the WIPI2 mutation did not show iron deposition, a characteristic feature of SENDA.…”

MitophAging: Mitophagy in Aging and Disease

“…The family member WIPI2 localizes in a phosphatidylinositol 3-phosphate-dependent manner to the autophagosomal membrane, where it facilitates ATG16L1 recruitment and LC3 lipidation (Dooley et al, 2014;Bakula et al, 2017). Recently, patients with mutations in the WIPI2 gene have been described with multisystemic clinical features, primarily, neurological and skeletal deficiencies that are characterized by severe mental retardation and short stature (Jelani et al, 2019). Notably, WIPI2 overexpression prevents age-related autophagy decline in dorsal root ganglion neurons (Stavoe et al, 2019).…”