The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2012; 90(2):295-300. DOI: 10.1016/j.ajhg.2011.11.031
Source: PubMed


Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412(∗). This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412(∗) PIGA has residual function. Transfection of a mutant p.Arg412(∗) PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412(∗)) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family.

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    • "(300868), PIGM (MIM 610293), PIGV (MIM 239300), PIGO (MIM 614749), PGAP2 (MIM 614207), PGAP3 (MIM 611801), PIGW (MIM 610275), PIGQ (MIM 605754), PIGL (MIM 280000), PIGN (MIM 614080), PIGT (MIM 610272), and PGAP1 (MIM 61655) [Almeida et al., 2006; Krawitz et al., 2010, 2012; Maydan et al., 2011; Freeze et al., 2012; Johnston et al., 2012; Ng et al., 2012; Hansen et al., 2013; Kvarnung et al., 2013; Chiyonobu et al., 2014; Howard et al., 2014; Martin et al., 2014; Murakami et al., 2014] "
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    ABSTRACT: Glycosylphosphatidylinositol (GPI) anchors tether proteins to the extracellular face of eukaryotic plasma membranes. Defects in the human GPI anchor biosynthetic pathway cause inherited GPI deficiencies (IGDs) characterized by multiple congenital anomalies: dysmorphic faces, developmental delay, hypotonia, and epilepsy. We report the case of a 6-year-old boy with severe psychomotor developmental delay, epilepsy, and decreased granulocyte surface expression of GPI-anchored protein that suggested autosomal recessive GPI deficiency. The case underwent target exome sequencing to screen for IGDs. Target exome sequencing of the proband identified an apparently homozygous c.808T > C (p.Ser270Pro) mutation in PIGN, a gene involved in the GPI anchor biosynthetic pathway. As his parents were expecting another child, genetic carrier screening was conducted for the parents. Direct sequencing of the parents identified a heterozygous c.808T > C PIGN mutation in the father but none in the mother. To identify the mother's mutation, we performed semi-quantitative real-time PCR of the PIGN exons and long PCR, identifying a microdeletion in PIGN (del exons 2-14). The proband had inherited this microdeletion from his mother. Prenatal diagnosis of the fetus revealed that it was a heterozygous carrier of the mother's pathogenic allele. Here, we report a sporadic case of inherited GPI deficiency with a PIGN mutation and the first case of prenatal diagnosis for GPI deficiency. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37397 · 2.16 Impact Factor
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    • "mutation was demonstrated in an in vitro cellular assay, evidence that the role of PIGA in GPI anchor biosynthesis is critical for normal central nervous system development [Johnston et al., 2012]. Germline mutations in several other genes affecting the GPI anchor biosynthesis pathway cause syndromes encompassing an increasingly broad range of phenotype with widely variable neurologic involvement, including a new subclass of congenital disorders of glycosylation [Jaeken, 2011]. "
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    ABSTRACT: Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36189 · 2.16 Impact Factor
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    • "The manuscript by Harakalova et al. [2013] in this issue of the Journal is a confirmation of the findings of our group, when we showed that a leaky null germline mutation in PIGA caused a devastating neurologic disorder with death in infancy [Johnston et al., 2012]. The phenotypes of the patients in Harakalova et al., [2013] and Johnston et al. [2012] are substantially similar both to each other and to the syndrome family [Brunner and van Driel, 2004] of disorders caused by mutations in other members of the PIG gene family. "
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    ABSTRACT: Two research groups have published reports on PIGA (phosphatidylinositol glycan class A) mutations that validate and extend our understanding of the range of phenotypes of this phenotypic spectrum. One report is primarily confirmatory of the discovery in 2012 that mutations in this gene cause a phenotype of dysmorphic features, neurologic manifestations, and biochemical perturbations. The second report describes an intriguing family with a phenotypically distinct neurological picture, distinguished primarily by CNS iron accumulation. These reports address important lessons in judging causality in the exome age and bear on the question of syndrome nomenclature. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36213 · 2.16 Impact Factor
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