bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2023‒07‒30
two papers selected by
Silvia Radenkovic
Frontiers in Congenital Disorders of Glycosylation Consortium
  1. GPI-anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?
  2. SLC5A1 Variants in Turkish Patients with Congenital Glucose-Galactose Malabsorption.
  1. Clin Genet. 2023 Jul 25.
    GPI-anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?
    Allan Bayat, Tobias Lindau, Angel Aledo-Serrano, Antonio Gil-Nagel, Ivo Barić, Dorotea Bartoniček, Josipa Mateševac, Danijela Petković Ramadža, Tamara Žigman, Silvija Pušeljić, Sanja Dorner, Caleb Bupp, Seth Devries, Rikke Steensbjerre Møller.
      Glycosylphosphatidylinositol anchoring disorders (GPI-ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA-encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI-ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI-ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI-AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI-AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI-AD. All were diagnosed with PIGA-encephalopathy and three had a disease-causing variant at the same residue. The literature reports five additional children with GPI-AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI-ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.
    Keywords:  GPI; GPIAD; PIGA; cardiomyopathy; genetics; glycosylphosphatidylinositol biosynthesis defects; heart; mortality
    DOI:  https://doi.org/10.1111/cge.14405
  2. Genes (Basel). 2023 Jun 27. pii: 1359. [Epub ahead of print]14(7):
    SLC5A1 Variants in Turkish Patients with Congenital Glucose-Galactose Malabsorption.
    Ferda Ö Hoşnut, Andreas R Janecke, Gülseren Şahin, Georg F Vogel, Naz G Lafcı, Paul Bichler, Thomas Müller, Lukas A Huber, Taras Valovka, Aysel Ü Aksu.
      Congenital glucose-galactose malabsorption is a rare autosomal recessive disorder caused by mutations in SLC5A1 encoding the apical sodium/glucose cotransporter SGLT1. We present clinical and molecular data from eleven affected individuals with congenital glucose-galactose malabsorption from four unrelated, consanguineous Turkish families. Early recognition and timely management by eliminating glucose and galactose from the diet are fundamental for affected individuals to survive and develop normally. We identified novel SLC5A1 missense variants, p.Gly43Arg and p.Ala92Val, which were linked to disease in two families. Stable expression in CaCo-2 cells showed that the p.Ala92Val variant did not reach the plasma membrane, but was retained in the endoplasmic reticulum. The p.Gly43Arg variant, however, displayed processing and plasma membrane localization comparable to wild-type SGLT1. Glycine-43 displays nearly invariant conservation in the relevant structural family of cotransporters and exchangers, and localizes to SGLT1 transmembrane domain TM0. p.Gly43Arg represents the first disease-associated variant in TM0; however, the role of TM0 in the SGLT1 function has not been established. In summary, we are expanding the mutational spectrum of this rare disorder.
    Keywords:  SGLT1; endoplasmic reticulum; glucose-galactose malabsorption; glycosylation; missense mutation; transmembrane domain
    DOI:  https://doi.org/10.3390/genes14071359
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