2. Academic Validation
  3. Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

  • J Med Genet. 2020 Apr;57(4):274-282. doi: 10.1136/jmedgenet-2019-106409.
Shereen Georges Ghosh 1 2,  Lu Wang 1 2,  Martin W Breuss 1 2,  Joshua D Green 3,  Valentina Stanley 1 2,  Xiaoxu Yang 1 2,  Danica Ross 1 2,  Bryan J Traynor 3 4,  Amal M Alhashem 5,  Matloob Azam 6,  Laila Selim 7,  Laila Bastaki 8,  Hanan I Elbastawisy 9,  Samia Temtamy 10,  Maha Zaki 11,  Joseph G Gleeson 12 13
Affiliations

Affiliations

  • 1 Neurosciences, University of California San Diego, La Jolla, California, USA.
  • 2 Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
  • 3 Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institutes of Health, Bethesda, Maryland, USA.
  • 4 Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
  • 5 Pediatrics, Prince Sultan Military Medical City, Riyadh, Al Riyadh, Saudi Arabia.
  • 6 Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.
  • 7 Pediatric Neurology, Cairo University, Cairo, Egypt.
  • 8 Kuwait Medical Genetics Centre, Maternity Hospital, Shuwaikh, Kuwait.
  • 9 Ophthalmic Genetics, Research Institute of Ophthalmology, Sulaibikhat, Egypt.
  • 10 Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
  • 11 Clinical Genetics, National Research Centre, Cairo, Egypt.
  • 12 Rady Children's Institute for Genomic Medicine, San Diego, California, USA [email protected].
  • 13 Department of Neuroscience and Pediatrics, Howard Hughes Medical Institute, La Jolla, California, USA.
PMID: 31586943 DOI: 10.1136/jmedgenet-2019-106409
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.

Keywords

ER stress; TMX2; microlissencephaly; protein disulfide isomerase; thioredoxin.

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