@article {956, title = {Recurrent homozygous damaging mutation in , encoding a protein disulfide isomerase, in four families with microlissencephaly.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {274-282}, abstract = {

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 (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 is an activator of cellular repeat expansion toxicity, patients showed no evidence of repeat expansions.

CONCLUSION: The c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of expansions. is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

}, keywords = {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, Whole Exome Sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106409}, author = {Ghosh, Shereen Georges and Wang, Lu and Breuss, Martin W and Green, Joshua D and Stanley, Valentina and Yang, Xiaoxu and Ross, Danica and Traynor, Bryan J and Alhashem, Amal M and Azam, Matloob and Selim, Laila and Bastaki, Laila and Elbastawisy, Hanan I and Temtamy, Samia and Zaki, MAH and Gleeson, Joseph G} }