bims-meglyc 2023-07-09 papers

Mol Genet Metab. 2023 Jun 19. pii: S1096-7192(23)00259-7. [Epub ahead of print]139(4): 107629

Metabolic adaptation of human skin fibroblasts to ER stress caused by glycosylation defect in PMM2-CDG.

L Zdrazilova, T Rakosnikova, N Himmelreich, N Ondruskova, M Pasak, M Vanisova, N Volfova, T Honzik, C Thiel, H Hansikova.

PMM2-CDG is the most prevalent type of congenital disorders of glycosylation (CDG). It is caused by pathogenic variants in the gene encoding phosphomannomutase 2 (PMM2), which converts mannose-6-phosphate to mannose-1-phosphate and thus activates this saccharide for further glycosylation processes. Defective glycosylation can lead to an abnormal accumulation of unfolded proteins in endoplasmic reticulum (ER) and cause its stress. The ER is a key compartment for glycosylation, and its connection and communication with mitochondria has been described extensively in literature. Their crosstalk is important for cell proliferation, calcium homeostasis, apoptosis, mitochondrial fission regulation, bioenergetics, autophagy, lipid metabolism, inflammasome formation and unfolded protein response. Therefore, in the present study we posed a question, whether defective glycosylation leads to bioenergetic disruption. Our data reveal possible chronic stress in ER and activated unfolded protein response via PERK pathway in PMM2-CDG fibroblasts. Presumably, it leads to bioenergetic reorganization and increased assembly of respiratory chain complexes into supercomplexes together with suppressed glycolysis in PMM2-CDG patient cells. These changes cause alterations in Krebs cycle, which is tightly connected to electron transport system in mitochondria. In summary, we present data showing metabolic adaptation of cells to glycosylation defect caused by various pathogenic variants in PMM2.

Keywords: ATP-production; Bioenergetic metabolism; ER stress; Glycolysis; Glycosylation; PMM2-CDG

DOI: https://doi.org/10.1016/j.ymgme.2023.107629

Birth Defects Res. 2023 Jul 08.

DPAGT1-CDG: Recurrent fetal death.

Huimin Tao, Yu Sun, Jingfang Zhai, Jiebin Wu.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a series of relatively uncommon genetic disorders, and variants in the dolichyl-phosphate N-acetylglucosamine-1-phosphotransferase (DPAGT1) gene can cause DPAGT1-CDG, which is characterized by multisystem abnormalities: failure to thrive, psychomotor retardation, seizures, etc. PATIENTS: Two fetuses in a nonconsanguineous family recurrently presented with irregular skull morphology, micrognathia, adduction and supination by prenatal ultrasound. They were finally found dead in utero. Pedigree whole exome sequencing revealed novel compound heterozygous variants in the DPAGT1 gene. We also reviewed 11 previous reports associated with DPAGT1-CDG.CONCLUSIONS: We report novel variants in the DPAGT1 gene in two fetuses from the same family with intrauterine death.

Keywords: DPAGT1; congenital disorders of glycosylation; genetic analysis; intrauterine fetal death; pedigree whole exome sequencing

DOI: https://doi.org/10.1002/bdr2.2219

Comput Struct Biotechnol J. 2023 ;21 3424-3436

New insights into the pathogenicity of TMEM165 variants using structural modeling based on AlphaFold 2 predictions.

Dominique Legrand, Mélissandre Herbaut, Zoé Durin, Guillaume Brysbaert, Muriel Bardor, Marc F Lensink, François Foulquier.

TMEM165 is a Golgi protein playing a crucial role in Mn2+ transport, and whose mutations in patients are known to cause Congenital Disorders of Glycosylation. Some of those mutations affect the highly-conserved consensus motifs E-φ-G-D-[KR]-[TS] characterizing the CaCA2/UPF0016 family, presumably important for the transport of Mn2+ which is essential for the function of many Golgi glycosylation enzymes. Others, like the G>R304 mutation, are far away from these motifs in the sequence. Until recently, the classical membrane protein topology prediction methods were unable to provide a clear picture of the organization of TMEM165 inside the cell membrane, or to explain in a convincing manner the impact of patient and experimentally-generated mutations on the transporter function of TMEM165. In this study, AlphaFold 2 was used to build a TMEM165 model that was then refined by molecular dynamics simulation with membrane lipids and water. This model provides a realistic picture of the 3D protein scaffold formed from a two-fold repeat of three transmembrane helices/domains where the consensus motifs face each other to form a putative acidic cation-binding site at the cytosolic side of the protein. It sheds new light on the impact of mutations on the transporter function of TMEM165, found in patients and studied experimentally in vitro, formerly and within this study. More particularly and very interestingly, this model explains the impact of the G>R304 mutation on TMEM165's function. These findings provide great confidence in the predicted TMEM165 model whose structural features are discussed in the study and compared to other structural and functional TMEM165 homologs from the CaCA2/UPF0016 family and the LysE superfamily.

Keywords: CDG; Glycosylation; Manganese; Modeling; TMEM165

DOI: https://doi.org/10.1016/j.csbj.2023.06.015