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01-09-2023 | Encephalopathy | Original Article

A novel homozygous PIGO mutation associated with severe infantile epileptic encephalopathy, profound developmental delay and psychomotor retardation: structural and 3D modelling investigations and genotype–phenotype correlation

Authors: Ameni Aguech, Lamia Sfaihi, Olfa Alila-Fersi, Roeya Kolsi, Abdelaziz Tlili, Thouraya Kammoun, Ahmed Fendri, Faiza Fakhfakh

Published in: Metabolic Brain Disease | Issue 8/2023

Abstract

The PIGO gene encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor serving to attach various proteins to their cell surface. These proteins are intrinsic for normal neuronal and embryonic development. In the current research work, a clinical investigation was conducted on a patient from a consanguineous family suffering from epileptic encephalopathy, characterized by severe seizures, developmental delay, hypotonia, ataxia and hyperphosphatasia. Molecular analysis was performed using Whole Exome Sequencing (WES). The molecular investigation revealed a novel homozygous variant c.1132C > T in the PIGO gene, in which a highly conserved Leucine was changed to a Phenylalanine (p.L378F). To investigate the impact of the non-synonymous mutation, a 3D structural model of the PIGO protein was generated using the AlphaFold protein structure database as a resource for template-based tertiary structure modeling. A structural analysis by applying some bioinformatic tools on both variants 378L and 378F models predicted the pathogenicity of the non-synonymous mutation and its potential functional and structural effects on PIGO protein. We also discussed the phenotypic and genotypic variability associated with the PIGO deficiency. To our best knowledge, this is the first report of a patient diagnosed with infantile epileptic encephalopathy showing a high elevation of serum alkaline phosphatase level. Our findings, therefore, widen the genotype and phenotype spectrum of GPI-anchor deficiencies and broaden the cohort of patients with PIGO associated epileptic encephalopathy with an elevated serum alkaline phosphatase level.

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Title: A novel homozygous PIGO mutation associated with severe infantile epileptic encephalopathy, profound developmental delay and psychomotor retardation: structural and 3D modelling investigations and genotype–phenotype correlation
Authors: Ameni Aguech
Lamia Sfaihi
Olfa Alila-Fersi
Roeya Kolsi
Abdelaziz Tlili
Thouraya Kammoun
Ahmed Fendri
Faiza Fakhfakh
Publication date: 01-09-2023
Publisher: Springer US
Keyword: Encephalopathy
Published in: Metabolic Brain Disease / Issue 8/2023
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-023-01276-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A novel homozygous PIGO mutation associated with severe infantile epileptic encephalopathy, profound developmental delay and psychomotor retardation: structural and 3D modelling investigations and genotype–phenotype correlation

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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