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

• Published in: American journal of human genetics Vol. 108; no. 6; pp. 1040 - 1052
• Main Authors: Ng, Bobby G., Sosicka, Paulina, Fenaille, François, Harroche, Annie, Vuillaumier-Barrot, Sandrine, Porterfield, Mindy, Xia, Zhi-Jie, Wagner, Shannon, Bamshad, Michael J., Vergnes-Boiteux, Marie-Christine, Cholet, Sophie, Dalton, Stephen, Dell, Anne, Dupré, Thierry, Fiore, Mathieu, Haslam, Stuart M., Huguenin, Yohann, Kumagai, Tadahiro, Kulik, Michael, McGoogan, Katherine, Michot, Caroline, Nickerson, Deborah A., Pascreau, Tiffany, Borgel, Delphine, Raymond, Kimiyo, Warad, Deepti, Flanagan-Steet, Heather, Steet, Richard, Tiemeyer, Michael, Seta, Nathalie, Bruneel, Arnaud, Freeze, Hudson H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.06.2021; Elsevier (Cell Press); Elsevier
• Subjects: Adult; Antiporters - genetics; Child; Child, Preschool; coagulopathy; Congenital Disorders of Glycosylation - etiology; Congenital Disorders of Glycosylation - pathology; congenital disordes of glycosylation; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; exome sequencing; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Genes, Dominant; Genetics; Glycosylation; Golgi pH; Humans; Infant; Infant, Newborn; Life Sciences; Liver Diseases - complications; Male; Monosaccharide Transport Proteins - genetics; Mutation; Pedigree; congenital disordes of glycosylation; glycosylation; exome sequencing; coagulopathy; Golgi pH
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2021.04.013

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.