Mutations in the phosphatidylinositol glycan C (<i>PIGC</i>) gene are associated with epilepsy and intellectual disability

Edvardson, Simon; Murakami, Yoshiko; Nguyen, Thi Tuyet Mai; Shahrour, Maher; St‐Denis, Anik; Shaag, Avraham; Damseh, Nadirah; Deist, Françoise Le; Bryceson, Yenan T.; Abu‐Libdeh, Bassam; Campeau, Philippe M.; Kinoshita, Taroh; Elpeleg, Orly

doi:10.1136/jmedgenet-2016-104202

Cited by 46 publications

(27 citation statements)

References 21 publications

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“…These individuals have a seizure disorder responding to anti‐epileptic drugs and severe global developmental delay or intellectual disability. ALP levels were normal …”

Section: Resultsmentioning

confidence: 99%

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

et al. 2018

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It is estimated that 0.5% of all mammalian proteins have a glycosylphosphatidylinositol (GPI)-anchor. GPI-anchored proteins (GPI-APs) play key roles, particularly in embryogenesis, neurogenesis, immune response and signal transduction. Due to their involvement in many pathways and developmental events, defects in the genes involved in their synthesis and processing can result in a variety of genetic disorders for which affected individuals display a wide spectrum of features. We compiled the clinical characteristics of 202 individuals with mutations in the GPI biosynthesis and processing pathway through a review of the literature. This review has allowed us to compare the characteristics and the severity of the phenotypes associated with different genes as well as highlight features that are prominent for each. Certain combinations, such as seizures with aplastic/hypoplastic nails or abnormal alkaline phosphatase levels suggest an inherited GPI deficiency, and our review of all clinical findings may orient the management of inherited GPI deficiencies.

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“…These individuals have a seizure disorder responding to anti‐epileptic drugs and severe global developmental delay or intellectual disability. ALP levels were normal …”

Section: Resultsmentioning

confidence: 99%

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

et al. 2018

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“…Also, rare GPIa negative cells are found in the blood and bone marrow of healthy individuals (Nafa et al, 1998;Hu et al, 2005). Germinal mutations in all but seven of the 26 GPIa pathway genes have been demonstrated to be the cause a number of genetic diseases from severe forms with multiple malformations to milder forms with intellectual disability (Kim et al, 2000;Kranz et al, 2001;Schenk et al, 2001;Garcia-Silva et al, 2004;Almeida et al, 2006;Lefeber et al, 2009;Krawitz et al, 2010Krawitz et al, , 2012Maydan et al, 2011;Barone et al, 2012;Ng et al, 2012;Thompson et al, 2012;Kvarnung et al, 2013;Chiyonobu et al, 2014;Martin et al, 2014;Nakamura et al, 2014;Nakashima et al, 2014;Ohba et al, 2014;Fujiwara et al, 2015;Ilkovski et al, 2015;Lam et al, 2015;Fleming et al, 2016;Hogrebe et al, 2016;Khayat et al, 2016;Makrythanasis et al, 2016;Edvardson et al, 2017;Johnstone et al, 2017;Nguyen et al, 2017Nguyen et al, , 2018Pagnamenta et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

Nicklas

Vacek

Carter

et al. 2019

Environ and Mol Mutagen

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During the First Gulf War (1991) over 100 servicemen sustained depleted uranium (DU) exposure through wound contamination, inhalation, and shrapnel. The Department of Veterans Affairs has a surveillance program for these Veterans which has included genotoxicity assays. The frequencies of glycosylphosphatidylinositol anchor (GPIa) negative (aerolysin resistant) cells determined by cloning assays for these Veterans are reported in Albertini RJ et al. (2019: Environ Mol Mutagen). Molecular analyses of the GPIa biosynthesis class A (PIGA) gene was performed on 862 aerolysin‐resistant T‐lymphocyte recovered isolates. The frequencies of different types of PIGA mutations were compared between high and low DU exposure groups. Additional molecular studies were performed on mutants that produced no PIGA mRNA or with deletions of all or part of the PIGA gene to determine deletion size and breakpoint sequence. One mutant appeared to be the result of a chromothriptic event. A significant percentage (>30%) of the aerolysin resistant isolates, which varied by sample year and Veteran, had wild‐type PIGA cDNA (no mutation). As described in Albertini RJ et al. (2019: Environ Mol Mutagen), TCR gene rearrangement analysis of these isolates indicated most arose from multiple T‐cell progenitors (hence the inability to find a mutation). It is likely that these isolates were the result of failure of complete selection against nonmutant cells in the cloning assays. Real‐time studies of GPIa resistant isolates with no PIGA mutation but with a single TCR gene rearrangement found one clone with a PIGV deletion and several others with decreased levels of GPIa pathway gene mRNAs implying mutation in other GPIa pathway genes. Environ. Mol. Mutagen. 60:470–493, 2019. © 2019 Wiley Periodicals, Inc.

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“…In regards to the second argument for mutation in PIGA being the only event that can produce GPIa deficiency because it is the only locus where a null phenotype can be produced by a single hit that is only true for individuals who are homozygous wild type for all other genes in the GPIa pathway. However, in humans, genetic conditions are known which are the result of homozygous mutations in one of the GPIa pathway genes (PIGC, PIGG, PIGH, PIGL, PIGM, PIGN, PIGO, PIGP, PIGQ, PIGT, PIGV, PIGW, PIGY, GPAA1, DPM1, DPM2, DPM3, and MPDU1) (Kim et al, 2000;Kranz et al, 2001;Schenk et al, 2001;Garcia-Silva et al, 2004;Almeida et al, 2006;Lefeber et al, 2009;Krawitz et al, 2010;Maydan et al, 2011;Barone et al, 2012;Krawitz et al, 2012;Ng et al, 2012;Thompson et al, 2012;Kvarnung et al, 2013;Chiyonobu et al, 2014;Martin et al, 2014;Nakamura et al, 2014;Nakashima et al, 2014;Ohba et al, 2014;Fujiwara et al, 2015;Ilkovski et al, 2015;Lam et al, 2015;Fleming et al, 2016;Hogrebe et al, 2016;Khayat et al, 2016;Makrythanasis et al, 2016;Edvardson et al, 2017;Johnstone et al, 2017;Nguyen et al, 2017;Nguyen et al, 2018;Pagnamenta et al, 2018). Clearly, heterozygosity for mutations will be present in the general population for each of these genes.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal study of t‐cell somatic mutations conferring glycosylphosphatidylinositol‐anchor deficiency in gulf war I veterans exposed to depleted uranium

Albertini

Nicklas

Vacek

et al. 2019

Environ and Mol Mutagen

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Fifty Veterans of the first Gulf War in 1991 exposed to depleted uranium (DU) were studied for glycosylphosphatidylinositol‐anchor (GPIa) deficient T‐cell mutants on three occasions during the years 2009, 2011, and 2013. GPIa deficiency was determined in two ways: cloning assays employing aerolysin selection and cytometry using the FLAER reagent for positive staining of GPIa cell surface proteins. Subsequent molecular analyses of deficient isolates recovered from cloning assays (Nicklas JA et al. [2019]: Environ Mol Mutagen) revealed apparent incomplete selection in some cloning assays, necessitating correction of original data to afford a more realistic estimate of GPIa deficient mutant frequency (MF) values. GPIa deficient variant frequencies (VFs) determined by cytometry were determined in the years 2011 and 2013. A positive but nonsignificant association was observed between MF and VF values determined on the same blood samples during 2013. Exposure to DU had no effect on either GPIa deficient MF or VFs. Environ. Mol. Mutagen. 60:494–504, 2019. © 2019 Wiley Periodicals, Inc.

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Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability

Abstract: joins the list of genes in which mutations result in defective biosynthesis of GPI anchoring, manifesting by global developmental delay and seizure disorder. The lack of specific biomarker dictates exome sequencing as the diagnostic procedure of choice in similar patients.

Cited by 46 publications

References 21 publications

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

Longitudinal study of t‐cell somatic mutations conferring glycosylphosphatidylinositol‐anchor deficiency in gulf war I veterans exposed to depleted uranium

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