De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood

Abstract

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.

Autophagy at the crossroads of catabolism and anabolism

“…Moreover, the loss of NCOA4 reduced the level of bioavailable intracellular iron in cells subjected to iron depletion and led to the profound accumulation of iron in splenic macrophages in vivo 44 . Defects in ferritin turnover may cause the neuro degenerative disorder static encephalopathy of childhood with neurodegeneration in adults (SENDA), which is characterized by the accumulation of iron deposits in basal ganglia due to mutations in the autophagy gene WD repeat domain phosphoinositide-interacting protein 4 (WDR45) 111,112 (TABLE 1). Overall, these results highlight the importance of autophagy for iron homeostasis and bioavailability, especially during iron depletion.…”

Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

“…2 Among published cases, 70% of patients suffered from epileptic seizures beginning after 3 months of age. 3,4 Early-onset epileptic encephalopathies (EOEE) form a group of severe epilepsies occurring in the first 3 months of life. Clinical signs include stormy seizures associated with an altered interictal electroencephalographic (EEG) pattern and abnormal neurological development.…”

Autophagy and human diseases

“…Human WDR45/WIPI4 shows a higher similarity to EPG-6 than to ATG-18, and loss of epg-6/ WIPI4 causes the accumulation of premature autophagic structures in both C. elegans and mammalian cells [19]. In fact, by using lymphoblastoid cell lines derived from SENDA patients, Saitsu et [13]. Since WDR45/WIPI4 is encoded by the X chromosome and one of the X chromosomes is subjected to X inactivation, female patients should possess mosaic loss of function of WDR45/WIPI4.…”