Dataset Information

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

ABSTRACT:

Purpose

Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Methods

We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system.

Results

Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder.

Conclusion

This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.

SUBMITTER: Tremblay-Laganiere C

PROVIDER: S-EPMC9900493 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

Tremblay-Laganière Camille C Maroofian Reza R Nguyen Thi Tuyet Mai TTM Karimiani Ehsan Ghayoor EG Kirmani Salman S Akbar Fizza F Ibrahim Shahnaz S Afroze Bushra B Doosti Mohammad M Ashrafzadeh Farah F Babaei Meisam M Efthymiou Stephanie S Christoforou Marilena M Sultan Tipu T Ladda Roger L RL McLaughlin Heather M HM Truty Rebecca R Mahida Sonal S Cohen Julie S JS Baranano Kristin K Ismail Fatima Y FY Patel Millan S MS Lehman Anna A Edmondson Andrew C AC Nagy Amanda A Walker Melissa A MA Mercimek-Andrews Saadet S Maki Yuta Y Sachdev Rani R Macintosh Rebecca R Palmer Elizabeth E EE Mancini Grazia M S GMS Barakat Tahsin Stefan TS Steinfeld Robert R Rüsch Christina T CT Stettner Georg M GM Wagner Matias M Wortmann Saskia B SB Kini Usha U Brady Angela F AF Stals Karen L KL Ismayilova Naila N Ellard Sian S Bernardo Danilo D Nugent Kimberly K McLean Scott D SD Antonarakis Stylianos E SE Houlden Henry H Kinoshita Taroh T Campeau Philippe M PM Murakami Yoshiko Y

Genetics in medicine : official journal of the American College of Medical Genetics 20210610 10

<h4>Purpose</h4>Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.<h4>Methods</h4>We describe 22 individuals from 19 unrela ...[more]

PMID: 34113002

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Project description:BackgroundClostridium sordellii can cause severe infections in animals and humans, the latter associated with trauma, toxic shock and often-fatal gynaecological infections. Strains can produce two large clostridial cytotoxins (LCCs), TcsL and TcsH, related to those produced by Clostridium difficile, Clostridium novyi and Clostridium perfringens, but the genetic basis of toxin production remains uncharacterised.ResultsPhylogenetic analysis of the genome sequences of 44 strains isolated from human and animal infections in the UK, US and Australia placed the species into four clades. Although all strains originated from animal or clinical disease, only 5 strains contained LCC genes: 4 strains contain tcsL alone and one strain contains tcsL and tcsH. Four toxin-positive strains were found within one clade. Where present, tcsL and tcsH were localised in a pathogenicity locus, similar to but distinct from that present in C. difficile. In contrast to C. difficile, where the LCCs are chromosomally localised, the C. sordellii tcsL and tcsH genes are localised on plasmids. Our data suggest gain and loss of entire toxigenic plasmids in addition to horizontal transfer of the pathogenicity locus. A high quality, annotated sequence of ATCC9714 reveals many putative virulence factors including neuraminidase, phospholipase C and the cholesterol-dependent cytolysin sordellilysin that are highly conserved between all strains studied.ConclusionsGenome analysis of C. sordellii reveals that the LCCs, the major virulence factors, are localised on plasmids. Many strains do not contain the LCC genes; it is probable that in several of these cases the plasmid has been lost upon laboratory subculture. Our data are consistent with LCCs being the primary virulence factors in the majority of infections, but LCC-negative strains may precipitate certain categories of infection. A high quality genome sequence reveals putative virulence factors whose role in virulence can be investigated.

Dataset Information

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

Purpose

Methods

Results

Conclusion

Publications

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

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