RESUMEN
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.
Asunto(s)
Ataxia Cerebelosa/genética , Predisposición Genética a la Enfermedad/genética , Trastornos del Neurodesarrollo/genética , Transporte de Proteínas/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Variación Genética , Humanos , Masculino , Linaje , Adulto Joven , Pez CebraRESUMEN
PURPOSE: To report isolated upgaze palsy in a patient with a dolichoectatic vertebrobasilar artery. CASE REPORT: We report a 48-year-old man who showed upgaze palsy and convergence insufficiency. The left vertebral artery and basilar artery were shown to be greatly expanded, elongated and tortuous in cranial magnetic resonance imaging (MRI). The vertebrobasilar artery runs along the sulcus basilaris superior to the pontomesencephalic junction. CONCLUSION: A dolichoectatic basilar artery may result in compression of midbrain structures related to vertical gaze.