Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy

VPS25

Biallelic hypomorphic VPS25 missense variants (ESCRT-II component) disrupting ESCRT-II interaction, cellular localization, small extracellular vesicle secretion and cargo

Five families whose newborns presented with a lethal neonatal encephalopathy (severe hypotonia, brain anomalies, epilepsy) were investigated by positional mapping, exome and trio exome sequencing. Families 1, 4 and 5, consanguineous and multiplex, share the same homozygous VPS25 missense variant; family 2 carries two missense variants in trans, one affecting the same residue, and family 3 another homozygous missense variant. Hypomorphic Vps25 mouse mutants recapitulate the brain malformation seen in patients. In mutant cells, ESCRT-II interaction and cellular localization are abnormal, multivesicular bodies are engorged and secretion of small extracellular vesicles such as exosomes is significantly reduced, with cargo lacking proteins required for axon protection and maintenance.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A new recessive neurodevelopmental disorder, carried by a gene already captured by any exome or genome: the task is now to recognize these missense variants at interpretation in a hypotonic newborn with epilepsy and brain anomalies. The convergence of five families, a mouse model and cellular assays is strong for a first report. The causal role of defective extracellular vesicles in neurodevelopmental disorders remains a mechanistic hypothesis, presented as such by the authors.

Analysis by Dr Thibaut Benquey