A novel PIGA mutation in a family with X-linked, early-onset epileptic encephalopathy

Kim, Young Ok; Yang, Jae Hyuk; Park, Chungoo; Kim, Seul-Kee; Kim, Myeong-Kyu; Shin, Myung-Geun; Woo, Young Jong

doi:10.1016/j.braindev.2016.02.008

Cited by 25 publications

(25 citation statements)

References 10 publications

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“…As shown in Supp. Table S2, 19 patients from 12 families with PIGA deficiency (MIM# 311770) have been reported to date (Belet et al., ; Fauth et al., ; Johnston et al., ; Joshi et al., ; Kato et al., ; Kim et al., ; Swoboda et al., ; Tarailo‐Graovac et al., ; van der Crabben et al., ). PIGA is involved in the initial step in GPI biosynthesis, whereas PIGO is involved in a later step.…”

Section: Resultsmentioning

confidence: 99%

Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties

et al. 2017

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Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.

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Section: Resultsmentioning

confidence: 99%

Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties

et al. 2017

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“…MCAHS comprises a group of genetically different disorders characterized by early onset forms of different types of epilepsies with poor prognosis, missing or minimal psychomotor development and often, early death (Table S2). The phenotypic series include individuals with PIGA (MIM 300868)[10, 13-15, 42-46], PIGN (MIM 614080)[12, 18, 47-53], and PIGT (MIM 615398)[11, 39, 54-57] mutations.…”

Section: Methods and Study Designmentioning

confidence: 99%

Characterization of Glycosylphosphatidylinositol Biosynthesis Defects by Clinical Features, Flow Cytometry, and Automated Image Analysis

Knaus

Pantel

Pendziwiat³

et al. 2017

Preprint

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“…Up to now there have been at least 15 reported genetic variants of PIGA in clinical PIGA deficiency cases with most of which having been experimentally proven as pathogenic variants (Figure c). All these reported disease‐associated variants are located in the coding exons, including 10 missense variants at conserved positions of PIGA protein (NP_002632.1: p.Arg77Leu, p.Pro93Leu, p.Arg119Trp, p.(Ala142Thr), p.(Lys143Glu), p.Asn179Tyr, p.Ile206Phe, p.(Ser330Asn), p.(Glu395Lys), p.(Ile451Thr)), one in‐frame deletion (p.(Leu344del)), two duplications causing frame‐shifts (p.(Ser24Lysfs*3), p.Tyr26Leufs*3), and one non‐sense variant (p.Arg412*) (Figure b) (Fokstuen et al., ; Joshi et al., ; Kim et al., ; Olson et al., ; Soden et al., ; Zhu et al., ). In addition, there has also been one de novo missense variant (p.(Leu355Ser)) which has PIGA deficiency phenotype (Trump et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Up to now there have been at least 15 reported genetic variants of PIGA in clinical PIGA deficiency cases with most of which having been experimentally proven as pathogenic variants (Figure 2c). All these reported diseaseassociated variants are located in the coding exons, including 10 missense variants at conserved positions of PIGA protein (NP_002632.1: p.Arg77Leu, p.Pro93Leu, p. (Figure 2b) (Fokstuen et al, 2016;Joshi et al, 2016;Kim et al, 2016;Olson et al, 2017;Soden et al, 2014;Zhu et al, 2015). In addition, there has also been one de novo missense variant (p.(Leu355Ser)) which has PIGA deficiency phenotype (Trump et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

Yang

Wang

Zhuo

et al. 2018

Molec Gen & Gen Med

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BackgroundGlycosylphosphatidylinositol (GPI) anchoring is a special type of protein posttranslational modification, by which proteins with diverse function are attached to cell membrane through a covalent linkage between the protein and the glycolipid. Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) is a key enzyme in GPI anchor biosynthesis, somatic mutations or genetic variants of which have been associated with paroxysmal nocturnal hemoglobinuria (PNH), or PIGA deficiency, respectively. More than 10 PIGA pathogenic or likely pathogenic variants have been reported in a wide spectrum of clinical syndromes of PIGA deficiency, including multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2).MethodsWhole‐exome sequencing (WES) was performed on two trios, that is., the proband's family and his affected maternal cousin's family, from a nonconsanguineous Chinese family pedigree with hypotonia‐encephalopathy‐seizures disease history and putative X‐linked recessive inheritance. Sanger sequencing for PIGA variant was performed on affected members as well as unaffected members in the family pedigree to verify its familial segregation.ResultsA novel likely pathogenic variant in PIGA was identified through comparative WES analysis of the two affected families. The single‐nucleotide substitution (NC_000023.9:g.15343279T>C) is located in intron 3 of the PIGA gene and within the splice acceptor consensus sequence (NM_002641.3:c.849‐5A>G). Even though we have not performed RNA studies, in silico tools predict that this intronic variant may alter normal splicing, causing a four base pair insertion which creates a frameshift and a premature stop codon at position 297 (NP_002632.1:p.(Arg283Serfs*15)). Sanger sequencing analysis of the extended family members confirmed the presence of the variant and its X‐linked inheritance.Conclusion WES data analysis along with familial segregation of a rare intronic variant are suggestive of a diagnosis of X‐liked PIGA deficiency with clinical features of MCAHS2.

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A novel PIGA mutation in a family with X-linked, early-onset epileptic encephalopathy

Cited by 25 publications

References 10 publications

Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties

Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties

Characterization of Glycosylphosphatidylinositol Biosynthesis Defects by Clinical Features, Flow Cytometry, and Automated Image Analysis

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

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