1. Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly
- Author
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Ghosh, Shereen Georges, Wang, Lu, Breuss, Martin W, Green, Joshua D, Stanley, Valentina, Yang, Xiaoxu, Ross, Danica, Traynor, Bryan J, Alhashem, Amal M, Azam, Matloob, Selim, Laila, Bastaki, Laila, Elbastawisy, Hanan I, Temtamy, Samia, Zaki, Maha, and Gleeson, Joseph G
- Subjects
Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Genetics ,Biological Sciences ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Neurosciences ,Brain Disorders ,Congenital Structural Anomalies ,Clinical Research ,Human Genome ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Amino Acid Sequence ,Child ,Child ,Preschool ,Consanguinity ,Endoplasmic Reticulum ,Exons ,Female ,Genetic Predisposition to Disease ,Homozygote ,Humans ,Male ,Membrane Proteins ,Microcephaly ,Mutation ,Protein Disulfide-Isomerases ,Protein Folding ,Thioredoxins ,Exome Sequencing ,TMX2 ,thioredoxin ,ER stress ,microlissencephaly ,protein disulfide isomerase ,Medical and Health Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.
- Published
- 2020