Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy
21 affiliations
- 1Biomedical Sciences Division, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900 Saudi Arabia
- 2Department of Translational Genomics, Genomic Medicine Centre of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- 3Program in Craniofacial Biology, Department of Orofacial Sciences, Department of Anatomy, Institute for Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA USA
- 4Institute of Human Genetics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, 5020 Austria
- 5KAUST Core Labs, KAUST, Thuwal, 23955-6900 Kingdom of Saudi Arabia
- 6Lifera Omics, Lifera Omics Innovation Boulevard St, KAFD, Al Aqeeq Dist., Riyadh, 13519 Saudi Arabia
- 7Division of Neonatology, Department of Pediatrics and Adolescent Medicine, Paracelsus Medical University, Salzburg, 5020 Austria
- 8Wellness and Preventative Medicine Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442 Saudi Arabia
- 9Department of Obstetrics and Gynecology, Paracelsus Medical University, Salzburg, 5020 Austria
- 10Department of Pediatrics, and Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, St. Louis, MO USA
- 11Department of Pediatrics, Saint Louis University School of Medicine, St Louis, MO USA
- 12Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- 13Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
- 14Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
- 15Department of Pediatrics, King Fahad Hospital of the University, Al-Khobar, Saudi Arabia
- 16Institute of Human Genetics, University of Regensburg, Regensburg, 93053 Germany
- 17Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, 93053 Germany
- 18Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD USA
- 19Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD USA
- 20College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- 21KAUST Center of Excellence for Smart Health (KCSH), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
Abstract
Background: The role of small extracellular vesicles (sEVs), such as exosomes, in cell-to-cell communication is increasingly recognized. Both during development and postnatally, sEVs have been shown to mediate a multitude of essential functions in the central nervous system. While abnormal sEV biogenesis has been observed in a number of neurodevelopmental disorders, a causal link has been largely lacking.
Methods: We clinically evaluated five families in which newborns presented with a novel neonatal-onset encephalopathy. Positional mapping, exome sequencing, and trio exome sequencing were utilized to identify the underlying genetic variants. Additionally, we utilized Vps25 hypomorphic mouse mutants and performed cellular assays to evaluate ESCRT-II interaction, cellular localization, and sEV secretion and cargo capacities.
Results: The observed lethal encephalopathy is characterized by severe hypotonia, brain anomalies, and epilepsy. In families 1, 4, and 5 (multiplex consanguineous), we identified a novel homozygous missense variant in VPS25 as the likely candidate. Family 2 comprises a simplex case with two missense variants in trans in VPS25, one of which impacts the same residue as in the other three families. Family 3 also comprises a simplex case where we revealed a homozygous missense variant. VPS25 is an essential component of ESCRT-II, itself required for sEV biogenesis. We show that Vps25 hypomorphic mouse mutants recapitulate the developmental brain malformation observed in patients. We also show that mutant VPS25 is associated with abnormal ESCRT-II interaction, abnormal cellular localization, and highly abnormal sEVs. Specifically, mutant cells displayed engorged multivesicular bodies and were significantly defective in their capacity to secrete sEVs such as exosomes, while secreted sEVs contained altered cargo, lacking vital proteins for axon protection and maintenance.
Conclusions: We report a novel neurodevelopmental disorder caused by biallelic hypomorphic variants in VPS25. The consistent impact of these variants on sEV biogenesis suggests a potential pathomechanism. While future cases will further delineate the phenotypic spectrum, these findings offer a new perspective on abnormal sEVs as drivers of human neurodevelopmental disorders.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13073-026-01693-z.
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BibTeX
@article{isaioglou2026recessive,
title = {{Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy}},
author = {Ioannis Isaioglou and Lama AlAbdi and Muhammad Tehseen and Yossef Lopez de los Santos and Mansour Aldehaiman and Gloria Lopez-Madrigal and Norah Altuwaijri and Viviana Hermosilla Aguayo and Anna Pleyers and Maya Ayach and Ashraf Al-Amoudi and Jing Kai and Vlad-Stefan Raducanu and Bader Alhaddad and Edda Hofstätter and Amani Al-Amodi and Mais O. Hashem and Hessa S. Alsaif and Claudius Fazelnia and Firdous Abdulwahab and Amal Jaafar and Tarfa Alshidi and Rana Helaby and Adriana M. Montaño and Kara C. Klemp and Ellen Totten and Wesam Kurdi and Saly Eltohamy and Hadeel Abdollah E. Alrukban and Bashayer Alawam and Licia Selleri and Davor Lessel and Dimitrios Kapogiannis and Samir M. Hamdan and Stephen R. Braddock and Fowzan S. Alkuraya and Jasmeen S. Merzaban},
journal = {Genome Medicine},
year = {2026},
month = sep,
doi = {10.1186/s13073-026-01693-z},
url = {https://doi.org/10.1186/s13073-026-01693-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy
AU - Ioannis Isaioglou
AU - Lama AlAbdi
AU - Muhammad Tehseen
AU - Yossef Lopez de los Santos
AU - Mansour Aldehaiman
AU - Gloria Lopez-Madrigal
AU - Norah Altuwaijri
AU - Viviana Hermosilla Aguayo
AU - Anna Pleyers
AU - Maya Ayach
AU - Ashraf Al-Amoudi
AU - Jing Kai
AU - Vlad-Stefan Raducanu
AU - Bader Alhaddad
AU - Edda Hofstätter
AU - Amani Al-Amodi
AU - Mais O. Hashem
AU - Hessa S. Alsaif
AU - Claudius Fazelnia
AU - Firdous Abdulwahab
AU - Amal Jaafar
AU - Tarfa Alshidi
AU - Rana Helaby
AU - Adriana M. Montaño
AU - Kara C. Klemp
AU - Ellen Totten
AU - Wesam Kurdi
AU - Saly Eltohamy
AU - Hadeel Abdollah E. Alrukban
AU - Bashayer Alawam
AU - Licia Selleri
AU - Davor Lessel
AU - Dimitrios Kapogiannis
AU - Samir M. Hamdan
AU - Stephen R. Braddock
AU - Fowzan S. Alkuraya
AU - Jasmeen S. Merzaban
PY - 2026
DA - 2026/09/14
JO - Genome Medicine
DO - 10.1186/s13073-026-01693-z
UR - https://doi.org/10.1186/s13073-026-01693-z
AB - Background: The role of small extracellular vesicles (sEVs), such as exosomes, in cell-to-cell communication is increasingly recognized. Both during development and postnatally, sEVs have been shown to mediate a multitude of essential functions in the central nervous system. While abnormal sEV biogenesis has been observed in a number of neurodevelopmental disorders, a causal link has been largely lacking. Methods: We clinically evaluated five families in which newborns presented with a novel neonatal-onset encephalopathy. Positional mapping, exome sequencing, and trio exome sequencing were utilized to identify the underlying genetic variants. Additionally, we utilized Vps25 hypomorphic mouse mutants and performed cellular assays to evaluate ESCRT-II interaction, cellular localization, and sEV secretion and cargo capacities. Results: The observed lethal encephalopathy is characterized by severe hypotonia, brain anomalies, and epilepsy. In families 1, 4, and 5 (multiplex consanguineous), we identified a novel homozygous missense variant in VPS25 as the likely candidate. Family 2 comprises a simplex case with two missense variants in trans in VPS25, one of which impacts the same residue as in the other three families. Family 3 also comprises a simplex case where we revealed a homozygous missense variant. VPS25 is an essential component of ESCRT-II, itself required for sEV biogenesis. We show that Vps25 hypomorphic mouse mutants recapitulate the developmental brain malformation observed in patients. We also show that mutant VPS25 is associated with abnormal ESCRT-II interaction, abnormal cellular localization, and highly abnormal sEVs. Specifically, mutant cells displayed engorged multivesicular bodies and were significantly defective in their capacity to secrete sEVs such as exosomes, while secreted sEVs contained altered cargo, lacking vital proteins for axon protection and maintenance. Conclusions: We report a novel neurodevelopmental disorder caused by biallelic hypomorphic variants in VPS25. The consistent impact of these variants on sEV biogenesis suggests a potential pathomechanism. While future cases will further delineate the phenotypic spectrum, these findings offer a new perspective on abnormal sEVs as drivers of human neurodevelopmental disorders. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13073-026-01693-z.
SN - 1756-994X
ER -