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Relevance to Autism

Goodman et al., 2021 identified 15 individuals with de novo coding variants in the TNPO2 gene who presented with global developmental delay, dysmorphic features, ophthalmologic abnormalities, and neurological features; behavioral deficits, including autism spectrum disorder or autistic features, were observed in 10 of 14 individuals in this study. Furthermore, functional studies in Drosophila in this study found that proband-associated variants were capable of causing more or less severe developmental phenotypes compared to wild-type TNPO2 when ectopically expressed, consistent with either loss-of-function or gain-of-function effects; one of the variants experimentally shown to result in loss-of-function effects was detected in an individual with autism spectrum disorder. De novo missense variants in the TNPO2 gene had previously been identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020).

Molecular Function

Probably functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila
DD, ID
ASD or autistic features, epilepsy/seizures
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1262R001 
 missense_variant 
 c.83A>G 
 p.Gln28Arg 
 De novo 
 NA 
  
 GEN1262R002 
 missense_variant 
 c.95A>G 
 p.Gln32Arg 
 De novo 
 NA 
  
 GEN1262R003 
 missense_variant 
 c.182C>G 
 p.Pro61Arg 
 De novo 
 NA 
  
 GEN1262R004 
 missense_variant 
 c.354G>C 
 p.Lys118Asn 
 De novo 
 NA 
  
 GEN1262R005 
 inframe_deletion 
 c.455_457del 
 p.Lys152del 
 De novo 
 NA 
  
 GEN1262R006 
 missense_variant 
 c.466G>A 
 p.Asp156Asn 
 De novo 
 NA 
  
 GEN1262R007 
 missense_variant 
 c.1108T>C 
 p.Trp370Arg 
 De novo 
 NA 
  
 GEN1262R008 
 missense_variant 
 c.1110G>C 
 p.Trp370Cys 
 De novo 
 NA 
  
 GEN1262R009 
 inframe_indel 
 c.1471_1474delinsCAAT 
 p.Lys491_Arg492delinsGlnTrp 
 De novo 
 NA 
  
 GEN1262R010 
 missense_variant 
 c.1541C>T 
 p.Pro514Leu 
 De novo 
 NA 
  
 GEN1262R011 
 missense_variant 
 c.1637C>T 
 p.Ala546Val 
 De novo 
 NA 
  
 GEN1262R012 
 missense_variant 
 c.1643C>T 
 p.Ser548Phe 
 De novo 
 NA 
  
 GEN1262R013 
 missense_variant 
 c.1794C>A 
 p.Phe598Leu 
 Familial 
 Maternal 
  
 GEN1262R014 
 inframe_deletion 
 c.1946_1957del 
 p.Ala649_Leu652del 
 De novo 
 NA 
  
 GEN1262R015 
 missense_variant 
 c.2181G>T 
 p.Trp727Cys 
 De novo 
 NA 
  
 GEN1262R016a 
 missense_variant 
 c.1592A>T 
 p.Gln531Leu 
 De novo 
 NA 
  
 GEN1262R016b 
 missense_variant 
 c.1583G>C 
 p.Gly528Ala 
 De novo 
 NA 
  
 GEN1262R017 
 missense_variant 
 c.1006C>T 
 p.Arg336Cys 
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion-Duplication
 28
 
19
Deletion-Duplication
 5
 
19
Deletion-Duplication
 3
 
19
Duplication
 1
 
19
Duplication
 1
 

No Animal Model Data Available

 

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