TY - JOUR
T1 - Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor
AU - Kumar, Raman
AU - Palmer, Elizabeth
AU - Gardner, Alison E.
AU - Carroll, Renee
AU - Banka, Siddharth
AU - Abdelhadi, Ola
AU - Donnai, Dian
AU - Elgersma, Ype
AU - Curry, Cynthia J.
AU - Gardham, Alice
AU - Suri, Mohnish
AU - Malla, Rishikesh
AU - Brady, Lauren Ilana
AU - Tarnopolsky, Mark
AU - Azmanov, Dimitar N.
AU - Atkinson, Vanessa
AU - Black, Michael
AU - Baynam, Gareth
AU - Dreyer, Lauren
AU - Hayeems, Robin Z.
AU - Marshall, Christian R.
AU - Costain, Gregory
AU - Wessels, Marja W.
AU - Baptista, Julia
AU - Drummond, James
AU - Leffler, Melanie
AU - Field, Michael
AU - Gecz, Jozef
PY - 2020/2/11
Y1 - 2020/2/11
N2 - Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals’ has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.
AB - Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals’ has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.
KW - intellectual disability
KW - microdeletion
KW - mRNA export
KW - neurodevelopmental disorders
KW - THOC2
UR - http://www.scopus.com/inward/record.url?scp=85083628262&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2020.00012
DO - 10.3389/fnmol.2020.00012
M3 - Article
C2 - 32116545
AN - SCOPUS:85083628262
SN - 1662-5099
VL - 13
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 12
ER -