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

ABSTRACT 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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Available from: Robert Brodsky, Sep 27, 2015
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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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    • "In addition, the present patient had severe accelerated linear growth and obesity. Although germline mutations were initially thought to be lethal early in development, the first report on a germline (nonsense) mutation in PIGA was recently been published in two siblings with a similar constellation of abnormalities [Johnston et al., 2012]. In concurrence with the present patient, one of these affected brothers described by Johnston et al. [2012] was also born prematurely with polyhydramnios, presumably due to decreased swallowing associated with poor fetal muscle strength. "
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    ABSTRACT: Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36184 · 2.16 Impact Factor
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