Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis

  • Pauline Elisabeth Schneeberger
  • Sheela Nampoothiri
  • Tess Holling
  • Dhanya Yesodharan
  • Malik Alawi
  • A S Knisely
  • Thomas Müller
  • Barbara Plecko
  • Andreas R Janecke (Geteilte/r Letztautor/in)
  • Kerstin Kutsche (Geteilte/r Letztautor/in)

Abstract

Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52, and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the TGN is mediated by GARP and endocytic recycling by EARP. Here we report two unrelated individuals with homozygous variants in VPS50, a splice variant (c.1978-1G>T) and an in-frame deletion (p.Thr608del). Both patients had severe developmental delay, postnatal microcephaly, corpus callosum hypoplasia, seizures and irritability, transient neonatal cholestasis, and failure to thrive. Light and transmission electron microscopy of liver from one revealed absence of gamma-glutamyltransferase at bile canaliculi, with mislocalization to basolateral membranes, and abnormal tight junctions. Using patient-derived fibroblasts, we identified reduced VPS50 protein accompanied by reduced levels of VPS52 and VPS53. While transferrin-receptor internalization rate was normal in cells of both patients, recycling of the receptor to the plasma membrane was significantly delayed. These data underscore the importance of VPS50 and/or the EARP complex in endocytic recycling and suggest an additional function in establishing cell polarity and trafficking between basolateral and apical membranes in hepatocytes. Individuals with biallelic hypomorphic variants in VPS50, VPS51 or VPS53 show an overarching neurodegenerative disorder with severe developmental delay, intellectual disability, microcephaly, early-onset epilepsy, and variable atrophy of the cerebellum, cerebrum, and/or brainstem. The term “GARP/EARP deficiency” designates disorders in such individuals.

Bibliografische Daten

OriginalspracheEnglisch
ISSN0006-8950
DOIs
StatusVeröffentlicht - 26.05.2021