De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment

Abstract

Summary The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.

VPS4A mutation in syndromic congenital hemolytic anemia without obvious signs of dyserythropoiesis

“…He was the first child of healthy blasts and red blood cells. 1,2 In our patient, the absence of obvious cytologic signs of CDA in bone marrow contrasts with the hematological findings in patients described by Seu et al, including one with the same mutation, which all had clear CDA. 1 This discrepancy could be due in part to the fact that patients reported by Seu et al were included through the congenital dyserythropoietic anemia registry for North America (CDAR).…”

“…2 Rodger et al focused on the neurodevelopmental disorder whereas hematological parameters were not extensively described. 1 The VPS4A protein is a vacuolar ATPase involved in reticulocyte maturation through exosome biogenesis. 3 We have independently identified another patient harboring a pathogenic VPS4A mutation.…”

“…Very recently, two research groups described a new neurodevelopmental syndrome with hematologic impairment, caused by de novo dominant mutations in the VPS4A gene. 1,2 Seu et al focused on three cases characterized by Congenital Dyserythropoietic Anemia (CDA) associated with a severe neurodevelopmental disorder (global developmental delay with microcephaly, retinal dystrophy and cerebellar hypoplasia; ref. 2 Rodger et al focused on the neurodevelopmental disorder whereas hematological parameters were not extensively described.…”

“…The same mutation had previously been found in five out of nine identified patients with VPS4Arelated disorder. 1,2 Functional testing of the p.R284W variant had been performed, showing a deleterious effect of mutated VPS4A protein on endosomal trafficking, formation of centrosome, primary cilium morphology and regulation of cell cycle in patients' fibroblasts and red blood cells. 1,2 In our patient, the absence of obvious cytologic signs of CDA in bone marrow contrasts with the hematological findings in patients described by Seu et al, including one with the same mutation, which all had clear CDA.…”

Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

“…In mouse cochlea, Ist1 is expressed in both hair cells and supporting cells (gEAR). Recently de novo VPS4A variants were identified to cause a multi-systemic neurodevelopmental disorder including sensorineural hearing loss due to the abnormal accumulation of IST1 protein in the limiting membrane of proband-derived fibroblasts and also in neuronal endosomes [76], suggesting that proper localization of IST1 is required for neuronal function. Taken together, our findings make IST1 an excellent candidate gene for nonsyndromic hearing loss.…”