Biallelic PIGM Coding Variant Causes Intractable Epilepsy and Intellectual Disability Without Thrombotic Events.
During the past two decades, an emerging group of genes coding for proteins involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis are being implicated in early-infantile epileptic encephalopathy. Amongst these, a hypomorphic promoter mutation in the mannosyltransferase-encoding PIGM gene was described in seven patients to date, exhibiting intractable absence epilepsy, portal and cerebral vein thrombosis and intellectual disability (ID). We describe here three siblings exhibiting intractable epilepsy and ID, found to harbor a homozygous c.224G>A p.(Arg75His) missense variant in PIGM, which segregated with the disease in the family. The variant is evolutionary conserved, extremely rare in general population databases and predicted to be deleterious. Structural modeling of the PIGM protein and the p.(Arg75His) variant indicates that it is located in a short luminal region of the protein, predicted to be hydrophilic. Functional prediction suggests that the entire local region is sensitive to mutations, with the p.(Arg75His) variant in particular. This is the first report of a PIGM coding variant, and the second variant altogether to be described affecting this gene. This phenotype differs from that of patients with the shared PIGM promoter mutation by lack of thrombotic events and no decrease in PIGM cDNA levels or CD59 expression on red blood cells.
Pubmed ID: 39425582 RIS Download
Research resources used in this publication
None foundAdditional research tools detected in this publication
- BD FACSDiva Software (RRID:SCR_001456)
- GATK (RRID:SCR_001876)
- SAMTOOLS (RRID:SCR_002105)
- dbSNP (RRID:SCR_002338)
- Jmol (RRID:SCR_003796)
- ModBase (RRID:SCR_004642)
- Picard (RRID:SCR_006525)
- MutationTaster (RRID:SCR_010777)
- MutPred (RRID:SCR_010778)
- SIFT (RRID:SCR_012813)
- Mutation Assessor (RRID:SCR_024502)
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BD FACSDiva Software (tool)
RRID:SCR_001456
A collection of tools for flow cytometer and application setup, data acquisition, and data analysis that help streamline flow cytometry workflows. It provides features to help users integrate flow systems into new application areas, including index sorting for stem cell and single-cell applications, as well as automation protocols for high-throughput and robotic laboratories.
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RRID:SCR_001876
A software package to analyze next-generation resequencing data. The toolkit offers a wide variety of tools, with a primary focus on variant discovery and genotyping as well as strong emphasis on data quality assurance. Its robust architecture, powerful processing engine and high-performance computing features make it capable of taking on projects of any size. This software library makes writing efficient analysis tools using next-generation sequencing data very easy, and second it's a suite of tools for working with human medical resequencing projects such as 1000 Genomes and The Cancer Genome Atlas. These tools include things like a depth of coverage analyzers, a quality score recalibrator, a SNP/indel caller and a local realigner. (entry from Genetic Analysis Software)
View all literature mentionsSAMTOOLS (tool)
RRID:SCR_002105
Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.
View all literature mentionsdbSNP (tool)
RRID:SCR_002338
Database as central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms. Distinguishes report of how to assay SNP from use of that SNP with individuals and populations. This separation simplifies some issues of data representation. However, these initial reports describing how to assay SNP will often be accompanied by SNP experiments measuring allele occurrence in individuals and populations. Community can contribute to this resource.
View all literature mentionsJmol (tool)
RRID:SCR_003796
An open-source Java viewer for chemical structures in 3D with features for chemicals, crystals, materials and biomolecules. It is cross-platform, running on Windows, Mac OS X, and Linux/Unix systems and features an applet, application, and systems integration component.
View all literature mentionsModBase (tool)
RRID:SCR_004642
A database of three-dimensional protein models calculated by comparative modeling. ModBase is organized into datasets, which are either available to the public, to the academic community, or to specific users. 20 unique amidohydrolase and 41 unique enolase structures have been determined have been included in the database.
View all literature mentionsPicard (tool)
RRID:SCR_006525
Java toolset for working with next generation sequencing data in the BAM format.
View all literature mentionsMutationTaster (tool)
RRID:SCR_010777
Evaluates disease-causing potential of sequence alterations.
View all literature mentionsMutPred (tool)
RRID:SCR_010778
Web application tool developed to classify an amino acid substitution as disease-associated or neutral in human.
View all literature mentionsSIFT (tool)
RRID:SCR_012813
Data analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsMutation Assessor (tool)
RRID:SCR_024502
Web server predicts functional impact of amino-acid substitutions in proteins, such as mutations discovered in cancer or missense polymorphisms. Functional impact is assessed based on evolutionary conservation of affected amino acid in protein homologs.
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