2. Academic Validation
  3. A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction

A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction

  • Am J Hum Genet. 2021 Jun 3;108(6):1040-1052. doi: 10.1016/j.ajhg.2021.04.013.
Bobby G Ng 1,  Paulina Sosicka 1,  François Fenaille 2,  Annie Harroche 3,  Sandrine Vuillaumier-Barrot 4,  Mindy Porterfield 5,  Zhi-Jie Xia 1,  Shannon Wagner 5,  Michael J Bamshad 6,  Marie-Christine Vergnes-Boiteux 7,  Sophie Cholet 2,  Stephen Dalton 8,  Anne Dell 9,  Thierry Dupré 10,  Mathieu Fiore 11,  Stuart M Haslam 9,  Yohann Huguenin 12,  Tadahiro Kumagai 5,  Michael Kulik 8,  Katherine McGoogan 13,  Caroline Michot 14,  Deborah A Nickerson 15,  Tiffany Pascreau 16,  Delphine Borgel 17,  Kimiyo Raymond 18,  Deepti Warad 19,  University of Washington Center for Mendelian Genomics (UW-CMG),  Heather Flanagan-Steet 20,  Richard Steet 20,  Michael Tiemeyer 5,  Nathalie Seta 10,  Arnaud Bruneel 21,  Hudson H Freeze 22
Affiliations

Affiliations

  • 1 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 2 Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, MetaboHUB, 91191 Gif sur Yvette, France.
  • 3 Hôpital Necker, Haemophilia Care Centre, 75015 Paris, France.
  • 4 AP-HP, Hôpital Bichat-Claude Bernard, Biochimie Métabolique et Cellulaire, 75018 Paris, France; INSERM U1149, Université de Paris, 75018 Paris, France.
  • 5 Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • 6 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 7 Laboratoire d'Hématologie, CHU de Bordeaux, 33604 Pessac, France.
  • 8 Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • 9 Department of Life Sciences, Imperial College London, SW7 2AZ London, UK.
  • 10 AP-HP, Hôpital Bichat-Claude Bernard, Biochimie Métabolique et Cellulaire, 75018 Paris, France.
  • 11 Laboratoire d'Hématologie, CHU de Bordeaux, 33604 Pessac, France; Centre de Référence des Pathologies Plaquettaires Constitutionnelles, CHU de Bordeaux, 33604 Pessac, France.
  • 12 Centre de Ressources et de Compétence des Maladies Hémorragiques Constitutionnelles, CHU de Bordeaux, 33076 Bordeaux, France.
  • 13 Medical Director of Hepatology Nemours Children's Specialty Care, Jacksonville, FL 32207, USA.
  • 14 Department of Clinical Genetics and Reference Centre for Constitutional Bone Diseases, INSERM U1163, Université de Paris, Imagine Institute, Necker-Enfants Malades Hospital, AP-HP, 75015, Paris, France.
  • 15 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 16 Laboratoire d'Hématologie Biologique, AP-HP, Hôpital Necker Enfants Malades, 75015 Paris, France.
  • 17 Laboratoire d'Hématologie Biologique, AP-HP, Hôpital Necker Enfants Malades, 75015 Paris, France; HITh, UMR_S 1176, INSERM, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
  • 18 Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 19 Division of Pediatric Hematology Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 20 JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 21 AP-HP, Hôpital Bichat-Claude Bernard, Biochimie Métabolique et Cellulaire, 75018 Paris, France; INSERM UMR1193, Université Paris-Saclay, 92290 Châtenay-Malabry, France.
  • 22 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 33964207 DOI: 10.1016/j.ajhg.2021.04.013
Abstract

SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane protein required for transporting glucose-6-phosphate (Glc-6P) into the ER. Once transported into the ER, Glc-6P is subsequently hydrolyzed by tissue-specific phosphatases to glucose and inorganic phosphate during times of glucose depletion. Pathogenic variants in SLC37A4 cause an established recessive disorder known as glycogen storage disorder 1b characterized by liver and kidney dysfunction with neutropenia. We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423∗), in SLC37A4; the affected individuals were from four unrelated families. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans, while N-glycans in fibroblasts and undifferentiated iPSC were normal. Due to the liver-specific nature of this disorder, we generated a CRISPR base-edited hepatoma cell line harboring the c.1267C>T (p.Arg423∗) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.

Keywords

Golgi pH; coagulopathy; congenital disordes of glycosylation; exome sequencing; glycosylation.

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