PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Tremblay‐Laganière, Camille; Maroofian, Reza; Nguyen, Thi Tuyet Mai; Karimiani, Ehsan Ghayoor; Kirmani, Salman; Akbar, Fizza; Ibrahim, Shahnaz; Afroze, Bushra; Doosti, Mohammad; Ashrafzadeh, Farah; Babaei, Meisam; Efthymiou, Stéphanie; Christoforou, Marilena; Sultan, Tipu; Ladda, Roger L.; McLaughlin, Heather; Truty, Rebecca; Mahida, Sonal; Cohen, Julie S.; Barañano, Kristin W.; Ismail, Fatima Y.; Patel, Millan S.; Lehman, Anna; Edmondson, Andrew C.; Nagy, Amanda; Walker, Melissa; Mercimek‐Andrews, Saadet; Maki, Yuta; Sachdev, Rani; Macintosh, Rebecca; Palmer, Elizabeth E.; Mancini, Grazia M.S.; Barakat, Tahsin Stefan; Steinfeld, Robert; Rüsch, Christina T.; Stettner, Georg M.; Wagner, Matias; Wortmann, Saskia B.; Kini, Usha; Brady, Angela; Stals, Karen; Ismayilova, Naila; Ellard, Sian; Bernardo, Danilo; Nugent, Kimberly; McLean, Scott; Antonarakis, Stylianos E.; Houlden, Henry; Kinoshita, Taroh; Campeau, Philippe M.; Murakami, Yoshiko

doi:10.1038/s41436-021-01215-9

Cited by 6 publications

(10 citation statements)

References 28 publications

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“…It is likely, therefore, that levels of a number of GPI‐APs on the affected individuals’ cells are decreased. Consistent with this, lower levels of several GPI‐APs in fibroblasts from two siblings with a homozygous nonsense PIGG variant have been reported (Zhao et al , 2017; Tremblay‐Laganière et al , 2021). Reduced levels of specific GPI‐APs may result in the clinical symptoms associated with PIGG ‐IGD, such as developmental delay, intellectual disability, seizures, and hypotonia.…”

Section: Discussionsupporting

confidence: 70%

“…PIGG activity on GPI‐APs can be measured by transfecting wild‐type or mutant PIGG cDNA into PIGO/PIGG‐ DKO cells, followed by FACS analysis (Fig EV5C). These are standard cellular and biochemical techniques, being relatively simple and sensitive, and may be further adapted for the prognosis of individuals with PIGG mutations (Tremblay‐Laganière et al , 2021).…”

Section: Resultsmentioning

confidence: 99%

“…Because PIGG deficiency mainly causes neurological defects, it is possible that GPI‐APs in brain have the alternative mode of GPI attachment happening more frequently than those in other tissues/organs. The question, what could be the functional difference between the two structures of brain GPI‐APs, remains, which leads to other questions as to why and how PIGG deficiency causes the various neurological symptoms (Makrythanasis et al , 2016; Zhao et al , 2017; Tremblay‐Laganière et al , 2021). Furthermore, there must be a reason why some proteins are expressed with this alternative structure.…”

Section: Discussionmentioning

confidence: 99%

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Ethanolamine‐phosphate on the second mannose is a preferential bridge for some GPI‐anchored proteins

et al. 2022

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Glycosylphosphatidylinositols (GPIs) are glycolipids that anchor many proteins (GPI-APs) on the cell surface. The core glycan of GPI precursor has three mannoses, which in mammals, are all modified by ethanolamine-phosphate (EthN-P). It is postulated that EthN-P on the third mannose (EthN-P-Man3) is the bridge between GPI and the protein and the second (EthN-P-Man2) is removed after GPI-protein attachment. However, EthN-P-Man2 may not be always transient, as mutations of PIGG, the enzyme that transfers EthN-P to Man2, result in inherited GPI deficiencies (IGDs), characterized by neuronal dysfunctions. Here, we show that EthN-P on Man2 is the preferential bridge in some GPI-APs, among them, the Ect-5'-nucleotidase and Netrin G2. We find that CD59, a GPI-AP, is attached via EthN-P-Man2 both in PIGB-knockout cells, in which GPI lacks Man3, and with a small fraction in wild-type cells. Our findings modify the current view of GPI anchoring and provide a mechanistic basis for IGDs caused by PIGG mutations.

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Section: Discussionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ethanolamine‐phosphate on the second mannose is a preferential bridge for some GPI‐anchored proteins

et al. 2022

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“…This is consistent with reports that some severe IGD cases show mitochondrial dysfunction (Tarailo-Graovac et al , 2015). CD73 expression is decreased in phosphatidylinositol glycan anchor biosynthesis class G (PIGG) knockout cells (Ishida et al , 2022) and some cases with null mutation of PIGG also showed decreased expression of CD73 and mitochondrial dysfunction (Tremblay-Laganière et al , 2021), suggesting that CD73 expression is important for uptake of vitamin B 2 in PIGG deficiency. Similar to HPP, some patients with IGD show decreased vitamin B 6 uptake and suffer from pyridoxine-dependent seizures (Kuki et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

Requirement of sequential hydrolysis by CD73 and ALP for uptake of vitamin B₂ into cells

Shichinohe

Kobayashi

Izumi

et al. 2022

Preprint

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Extracellular hydrolysis of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) to riboflavin is thought to be important for cellular uptake of vitamin B2 because FAD and FMN are hydrophilic and do not pass the plasma membrane. However, it is not clear whether FAD and FMN are hydrolyzed by cell surface enzymes for vitamin B2 uptake. Here, we show that in human cells, FAD, a major form of vitamin B2 in plasma, is hydrolyzed by CD73 (also called ecto-5′ nucleotidase) to FMN, then FMN is hydrolyzed by alkaline phosphatase to riboflavin, which is efficiently imported into cells. This process is impaired on the surface of glycosylphosphatidylinositol (GPI)-deficient cells due to lack of these GPI-anchored enzymes. During culture of GPI-deficient cells with FAD or FMN, hydrolysis of these forms of vitamin B2, intracellular levels of vitamin B2, vitamin B2-dependent pyridoxal 5′-phosphate formation, and mitochondrial functions were significantly decreased compared with those in GPI-restored cells. These results suggest that inefficient uptake of vitamin B2 might account for mitochondrial dysfunction seen in some cases of inherited GPI deficiency.

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“…Such variation in affected GPI-APs is observed in other GPI biosynthesis disorders, where the specific gene and mutation influence the pattern of GPI-AP disturbance. [22][23][24][25] It is highly likely that these SLC6A7 and MPPE1 variants contribute to the observed clinical phenotype. Both SLC6 transportopathies and inherited disorders of GPI deficiency are associated with a broad range of neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

et al. 2022

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PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Cited by 6 publications

References 28 publications

Ethanolamine‐phosphate on the second mannose is a preferential bridge for some GPI‐anchored proteins

Ethanolamine‐phosphate on the second mannose is a preferential bridge for some GPI‐anchored proteins

Requirement of sequential hydrolysis by CD73 and ALP for uptake of vitamin B₂ into cells

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

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PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Cited by 6 publications

References 28 publications

Ethanolamine‐phosphate on the second mannose is a preferential bridge for some GPI‐anchored proteins

Ethanolamine‐phosphate on the second mannose is a preferential bridge for some GPI‐anchored proteins

Requirement of sequential hydrolysis by CD73 and ALP for uptake of vitamin B2 into cells

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

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Requirement of sequential hydrolysis by CD73 and ALP for uptake of vitamin B₂ into cells