Background Protein 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.
Methods Eight 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.
Results An 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.
Conclusion The 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.
- ER stress
- protein disulfide isomerase
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Contributors JGG designed the research; SGG, LW, JDG and BJT performed the research; MWB and DR conducted the mouse work and analysis; VS, AMA, MA, LS, LB, HIE, ST and MZ collected the patient samples and XY performed the bioinformatics analysis; SGG and JGG analysed the data and wrote the paper.
Funding SGG was sponsored by the Ruth L. Kirschstein Institutional National Research Service Award (T32 GM008666) from the National Institute on Deafness and Other Communication Disorders and by award F31HD095602 from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Broad Institute funded E. Lander and D. MacArthur (U54HG003067 and UM1HG008900, respectively) and the Yale Center for Mendelian Disorders (U54HG006504 to M. Gunel). This work was supported by NIH grants R01NS048453, R01NS052455, the Simons Foundation Autism Research Initiative and Howard Hughes Medical Institute (to JGG). This work was supported in part by the Intramural Research Programmes of the NIH, National Institute on Aging (Z01-AG000949-02 to BJT). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 3 March 2018.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Institutional Review Board at the respective host institution.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open-access repository. See study accession: phs000288.v2.p2 on the the database of Genotypes and Phenotypes (dbGaP).