Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

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Abstract: Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson’s disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: Brain. - 144, 3 (2021) , 769–780, ISSN: 1460-2156

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2021

Creator: Sanderson, Leslie E.
Lanko, Kristina
Alsagob, Maysoon
Almass, Rawan
Al-Ahmadi, Nada
Najafi, Maryam
Antony, Dinu
Schmidts, Miriam
Barakat, Tahsin Stefan
Ham, Tjakko J. van
Kaya, Namik

DOI: 10.1093/brain/awaa459

URN: urn:nbn:de:bsz:25-freidok-1943348

Rights: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:22 AM CEST

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Associated

Sanderson, Leslie E.
Lanko, Kristina
Alsagob, Maysoon
Almass, Rawan
Al-Ahmadi, Nada
Najafi, Maryam
Antony, Dinu
Schmidts, Miriam
Barakat, Tahsin Stefan
Ham, Tjakko J. van
Kaya, Namik
Universität

Time of origin

2021

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Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

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Clinical and neuroradiological spectrum of biallelic variants in NOTCH3

Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy

The many faces of congenital anomalies of the kidney and urinary tract

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

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The many faces of congenital anomalies of the kidney and urinary tract

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The many faces of congenital anomalies of the kidney and urinary tract

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