|Title||Recurrent homozygous damaging mutation in , encoding a protein disulfide isomerase, in four families with microlissencephaly.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Ghosh, SGeorges, Wang, L, Breuss, MW, Green, JD, Stanley, V, Yang, X, Ross, D, Traynor, BJ, Alhashem, AM, Azam, M, Selim, L, Bastaki, L, Elbastawisy, HI, Temtamy, S, Zaki, MAH, Gleeson, JG|
|Journal||J Med Genet|
|Date Published||2020 04|
|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|
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.
|Alternate Journal||J Med Genet|
|PubMed Central ID||PMC7405652|
|Grant List||UM1 HG008900 / HG / NHGRI NIH HHS / United States |
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
S10 OD018521 / OD / NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
Z01 AG000949 / Im / Intramural NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
T32 GM008666 / GM / NIGMS NIH HHS / United States
F31 HD095602 / HD / NICHD NIH HHS / United States