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

Ghosh, Shereen G.; Wang, Lu; Breuss, Martin; Green, Joshua D; Stanley, Valentina; Yang, Xiaoxu; Ross, Danica; Traynor, Bryan J.; Alhashem, Amal; Azam, Matloob; Selim, Laila; Bastaki, Lailá; Elbastawisy, Hanan I; Temtamy, Samia; Zaki, Maha S.; Gleeson, Joseph G.

doi:10.1136/jmedgenet-2019-106409

Cited by 9 publications

(14 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in TMX2 coding gene, TMX2, cause microcephaly accompanied by lissencephaly, cortical polymicrogyria, and other cell migration defects (25,82). Even though the pathogenic mechanism associated to TMX2 mutants remains unknown, it may reflect disturbed redox regulation at mitochondria-ER contact sites resulting in impaired energy production (25).…”

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system

Medinas¹,

Rozas²,

Hetz³

2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system

Medinas¹,

Rozas²,

Hetz³

2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Consistently with its high expression in brain tissue, missense mutations of TMX2 have recently been associated with brain developmental abnormalities [41] and microlissencephaly [43], a rare congenital brain disorder [44]. This phenotype could result from a loss of the protective role of TMX2 from ER stresses [45], which represents an important concurrent cause of neuronal death [46].…”

Section: Tmx2 and Its Cytosolic Active Sitementioning

confidence: 90%

Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5

Guerra

Molinari

2020

Cells

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) is site of synthesis and maturation of membrane and secretory proteins in eukaryotic cells. The ER contains more than 20 members of the Protein Disulfide Isomerase (PDI) family. These enzymes regulate formation, isomerization and disassembly of covalent bonds between cysteine residues. As such, PDIs ensure protein folding, which is required to attain functional and transport-competent structure, and protein unfolding, which facilitates dislocation of defective gene products across the ER membrane for ER-associated degradation (ERAD). The PDI family includes over a dozen of soluble members and few membrane-bound ones. Among these latter, there are five PDIs grouped in the thioredoxin-related transmembrane (TMX) protein family. In this review, we summarize the current knowledge on TMX1, TMX2, TMX3, TMX4 and TMX5, their structural features, regulation and roles in biogenesis and control of the mammalian cell’s proteome.

show abstract

“…In addition, deletion of any one of the four consecutive G residues would create an indistinguishable frameshift allele. Recurrent variants at sites of homopolymeric G/C nucleotides have been identified in several disorders with monoallelic 13,14 or biallelic 15 inheritance.…”

Section: Discussionmentioning

confidence: 99%

A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features

Shao

Straussberg

Ahmed

et al. 2021

Genetics in Medicine

View full text Add to dashboard Cite

Purpose The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10. Methods Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry. Results A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein. Conclusion We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.

show abstract

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

Cited by 9 publications

References 35 publications

Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system

Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system

Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5

A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features

Contact Info

Product

Resources

About