Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly
Year: 2019
Type: article
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 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.
Source: Journal of Medical Genetics
Institutions: University of California San Diego, Rady Children's Institute for Genomic Medicine, National Institutes of Health, Johns Hopkins University, Riyadh Armed Forces Hospital, Wah Medical College, Cairo University, Research Institute of Ophthalmology, National Research Centre, Howard Hughes Medical Institute
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Simons Foundation, National Institutes of Health, National Human Genome Research Institute, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Yale Center for Mendelian Disorders, G1609525565, G1610708064, Molecular Characterization of Joubert Syndrome, Large Scale Sequencing and Analysis of Genomes, G2736151378, G2795716607, G3245471538, G5668452123, High Performance Computing Instrumentation for the Yale Center for Genome Analysi, University of California San Diego Neuroscience Microscopy Imaging Core, G66076379, Molecular mechanisms of the ADPRHL2-mediated pediatric neurodegenerative disease, G8849460995, G9000108620, Molecular Characterization of Pontocerebellar Hypoplasia
OpenAlex ID: W2978229137