2. Academic Validation
  3. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings

Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings

  • Am J Hum Genet. 2021 Nov 4;108(11):2130-2144. doi: 10.1016/j.ajhg.2021.09.012.
Matthew P Wilson 1,  Alejandro Garanto 2,  Filippo Pinto E Vairo 3,  Bobby G Ng 4,  Wasantha K Ranatunga 5,  Marina Ventouratou 6,  Melissa Baerenfaenger 7,  Karin Huijben 8,  Christian Thiel 9,  Angel Ashikov 7,  Liesbeth Keldermans 6,  Erika Souche 6,  Sandrine Vuillaumier-Barrot 10,  Thierry Dupré 10,  Helen Michelakakis 11,  Agata Fiumara 12,  James Pitt 13,  Susan M White 14,  Sze Chern Lim 13,  Lyndon Gallacher 14,  Heidi Peters 15,  Daisy Rymen 16,  Peter Witters 16,  Antonia Ribes 17,  Blai Morales-Romero 17,  Agustí Rodríguez-Palmero 18,  Diana Ballhausen 19,  Pascale de Lonlay 20,  Rita Barone 21,  Mirian C H Janssen 22,  Jaak Jaeken 16,  Hudson H Freeze 4,  Gert Matthijs 6,  Eva Morava 23,  Dirk J Lefeber 24
Affiliations

Affiliations

  • 1 Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium. Electronic address: matthew.wilson@kuleuven.be.
  • 2 Department of Pediatrics, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 3 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 4 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 5 Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 6 Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
  • 7 Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 8 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 9 Center for Child and Adolescent Medicine, Department Pediatrics I, Heidelberg University, 69120 Heidelberg, Germany.
  • 10 AP-HP, Biochimie Métabolique et Cellulaire, Hôpital Bichat-Claude Bernard, and Université de Paris, Faculté de Médecine Xavier Bichat, INSERM U1149, CRI, Paris, France.
  • 11 Department Enzymology and Cellular Function, Institute of Child Health, 11527 Athens, Greece.
  • 12 Pediatric Unit, Regional Referral Center for Inherited Metabolic Disease, Department of Clinical and Experimental Medicine University of Catania, 95123 Catania, Italy.
  • 13 Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
  • 14 Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
  • 15 Department of Metabolic Medicine, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
  • 16 Department of Pediatrics, Center for Metabolic Diseases, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 17 Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, 08036 Barcelona, Spain.
  • 18 Department of Pediatrics, Paediatric Neurology Unit, University Hospital Germans Trias i Pujol, CIBERER, 08916 Badalona, Spain.
  • 19 Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, 1011 Lausanne, Switzerland.
  • 20 Necker Hospital, APHP, Reference Center for Inborn Errors of Metabolism, University of Paris, Paris, France; Inserm UMR_S1163, Institut Imagine, 75015 Paris, France.
  • 21 Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
  • 22 Department of Pediatrics, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Department of Internal Medicine, Radboud Center for Mitochondrial Medicine, Radboud University, Nijmegen Medical Center, 65225 Nijmegen, the Netherlands.
  • 23 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Metabolic Medicine, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
  • 24 Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, 6525 Nijmegen, the Netherlands. Electronic address: dirk.lefeber@radboudumc.nl.
PMID: 34653363 DOI: 10.1016/j.ajhg.2021.09.012
Abstract

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of Carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.

Keywords

congenital disorders of glycosylation; dominant inheritance; glycosylation; oligosaccharyltransferase complex.

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