Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined Nonketotic Hyperglycinemia and Lipoate Deficiency

  • Laura Arribas-Carreira (Geteilte/r Erstautor/in)
  • Cristina Dallabona (Geteilte/r Erstautor/in)
  • Michael A Swanson (Geteilte/r Erstautor/in)
  • Joseph Farris (Geteilte/r Erstautor/in)
  • Elsebet Østergaard
  • Konstantinos Tsiakas
  • Maja Hempel
  • Cecile Aquaviva-Bourdain
  • Stefanos Koutsoukos
  • Nicholas V Stence
  • Martina Magistrati
  • Elaine B Spector
  • Kathryn Kronquist
  • Mette Christensen
  • Helena G Karstensen
  • René G Feichtinger
  • Melanie T Achleitner
  • J Lawrence Merritt
  • Belén Pérez
  • Magdalena Ugarte
  • Stephanie Grünewald
  • Anthony R Riela
  • Natalia Julve
  • Jean-Baptiste Arnoux
  • Kasturi Haldar
  • Claudia Donnini
  • René Santer
  • Allan M Lund (Geteilte/r Letztautor/in)
  • Johannes A Mayr (Geteilte/r Letztautor/in)
  • Pilar Rodriguez-Pombo (Geteilte/r Letztautor/in)
  • Johan L K Van Hove (Geteilte/r Letztautor/in)

Abstract

Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293-1insT, one deletion c.122_(228 + 1_229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.

Bibliografische Daten

OriginalspracheEnglisch
ISSN0964-6906
DOIs
StatusVeröffentlicht - 06.03.2023

Anmerkungen des Dekanats

© The Author(s) 2022. Published by Oxford University Press.

PubMed 36190515