Abstract
Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.
| Original language | English |
|---|---|
| Pages (from-to) | 1126-1138 |
| Number of pages | 13 |
| Journal | Human Mutation |
| Volume | 39 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 08-2018 |
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All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)
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Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. / The Broad CMG.
In: Human Mutation, Vol. 39, No. 8, 08.2018, p. 1126-1138.Research output: Contribution to journal › Article
TY - JOUR
T1 - Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery
AU - The Broad CMG
AU - Kumar, Raman
AU - Gardner, Alison
AU - Homan, Claire C.
AU - Douglas, Evelyn
AU - Mefford, Heather
AU - Wieczorek, Dagmar
AU - Lüdecke, Hermann Josef
AU - Stark, Zornitza
AU - Sadedin, Simon
AU - Nowak, Catherine Bearce
AU - Douglas, Jessica
AU - Parsons, Gretchen
AU - Mark, Paul
AU - Loidi, Lourdes
AU - Herman, Gail E.
AU - Mihalic Mosher, Theresa
AU - Gillespie, Meredith K.
AU - Brady, Lauren
AU - Tarnopolsky, Mark
AU - Madrigal, Irene
AU - Eiris, Jesús
AU - Domènech Salgado, Laura
AU - Rabionet, Raquel
AU - Strom, Tim M.
AU - Ishihara, Naoko
AU - Inagaki, Hidehito
AU - Kurahashi, Hiroki
AU - Dudding-Byth, Tracy
AU - Palmer, Elizabeth E.
AU - Field, Michael
AU - Gecz, Jozef
PY - 2018/8
Y1 - 2018/8
N2 - Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.
AB - Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.
UR - http://www.scopus.com/inward/record.url?scp=85049833042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049833042&partnerID=8YFLogxK
U2 - 10.1002/humu.23557
DO - 10.1002/humu.23557
M3 - Article
C2 - 29851191
AN - SCOPUS:85049833042
VL - 39
SP - 1126
EP - 1138
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 8
ER -