Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy

Kuwayama, Ryoko; Suzuki, Keiichiro; Nakamura, Jun; Aizawa, Emi; Yoshioka, Yoshichika; Ikawa, Masahito; Nabatame, Shin; Inoue, Ken; Shimmyo, Yoshiari; Ozono, Keiichi; Kinoshita, Taroh; Murakami, Yoshiko

doi:10.1038/s41467-022-30847-x

Cited by 8 publications

(11 citation statements)

References 56 publications

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“…18,19 Glycocalyceal dysfunction has been previously suggested as a pathogenic mechanism in a cohort of patients with congenital disorders of glycosylation, including a patient with PIGN-CDG reported by Brucker et al for whom fresh frozen plasma and protein C concentrate infusions were given, with the rationale of supporting the endothelial glycocalyx during acute illnesses, with excellent results. 20 It is possible that further studies, especially using the recently validated murine model for PIGO deficiency, 21 will better delineate the role of the glycocalyx and the etiology of intestinal dysfunction in these patients and provide therapeutic insights for addressing this issue.…”

Section: Discussionmentioning

confidence: 99%

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

Starosta,

Kerashvili,

Pruitt

et al. 2023

JIMD Reports

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The phosphatidylinositol glycan anchor biosynthesis class O protein (PIGO) enzyme is an important step in the biosynthesis of glycosylphosphatidylinositol (GPI), which is essential for the membrane anchoring of several proteins. Bi‐allelic pathogenic variants in PIGO lead to a congenital disorder of glycosylation (CDG) characterized by global developmental delay, an increase in serum alkaline phosphatase levels, congenital anomalies including anorectal, genitourinary, and limb malformations in most patients; this phenotype has been alternately called “Mabry syndrome” or “hyperphosphatasia with impaired intellectual development syndrome 2.” We report a 22‐month‐old female with PIGO deficiency caused by novel PIGO variants. In addition to the Mabry syndrome phenotype, our patient's clinical picture was complicated by intermittent hypoglycemia with signs of functional hyperinsulinism, severe secretory diarrhea, and osteopenia with a pathological fracture, thus, potentially expanding the known phenotype of this disorder, although more studies are necessary to confirm these associations. We also provide an updated review of the literature, and propose unifying the nomenclature of PIGO deficiency as “PIGO‐CDG,” which reflects its pathophysiology and position in the broad scope of metabolic disorders and congenital disorders of glycosylation.

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Section: Discussionmentioning

confidence: 99%

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

Starosta,

Kerashvili,

Pruitt

et al. 2023

JIMD Reports

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“…This is consistent with reports that some severe IGD cases show mitochondrial dysfunction ( 28 ). In future, we are planning to analyze the metabolic conditions in vivo using IGD model mice ( 29 ). CD73 expression is decreased in phosphatidylinositol glycan anchor biosynthesis class G (PIGG) KO cells ( 30 ) and some cases with null mutation of PIGG also showed decreased expression of CD73 and mitochondrial dysfunction ( 31 ), suggesting that CD73 expression is important for uptake of vitamin B 2 in PIGG deficiency.…”

Section: Discussionmentioning

confidence: 99%

Sequential hydrolysis of FAD by ecto-5′ nucleotidase CD73 and alkaline phosphatase is required for uptake of vitamin B2 into cells

Shichinohe¹,

Kobayashi²,

Izumi³

et al. 2022

Journal of Biological Chemistry

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“…We used two software packages to evaluate cellularity and nuclear morphology: Hybrid Cell Count (BZ‐X800, Keyence) 21 and QuPath (version 0.3.2; an open‐source software for digital pathology images) 22 . For the Hybrid Cell Count, we took three HPFs per case carrying the greatest cell density at a glance, and semiautomatically analyzed them for the density and morphological parameters as follows: nuclear area, roundness, and circularity calculated, respectively, by the following equations:

Roundness = \frac{Diametermax . - Diameter \min .}{2}; Circularity = \frac{4 π \times Area}{Perimete r^{2}}

.…”

Section: Methodsmentioning

confidence: 99%

Prognostic value of nuclear morphometry in myxoid liposarcoma

et al. 2023

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Myxoid liposarcoma (MLS) accounts for 20%‐30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization/International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software‐based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high–nuclear‐grade group according to the modified Fuhrman grading system exhibited a significantly poor disease‐free survival (hazard ratio: 4.43; 95% confidence interval: 0.9‐22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high‐grade group ( p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density) but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high‐grade group significantly expressed the cell cycle–related genes (such as FOXM1 , PLK1 , and CDK1 ). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis.

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Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy

Cited by 8 publications

References 56 publications

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

PIGO‐CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations

Sequential hydrolysis of FAD by ecto-5′ nucleotidase CD73 and alkaline phosphatase is required for uptake of vitamin B2 into cells

Prognostic value of nuclear morphometry in myxoid liposarcoma

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