Current understanding of thap12
Thap12 Variants
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Predictions show these variants to be damaging to the protein structure/function.
No pathogenic or likely pathogenic variants in known disease genes that would explain the phenotype were identified in either sibling.
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THAP12 is an upstream regulator of interferon-induced serine/threonine protein kinase R. THAP12 has been shown to phosphorylate EIF2AK2, an IFN-induced serine/threonine-protein kinase has been recently associated (Tier 1 candidate) with a disorder of neurodevelopment (Baylor UDN, 2020), with clinical features similar to this case
The gene is depleted for protein-truncating variants in the general population, with a probability of loss-of-function intolerance score of 0.97.
The THAP domain is evolutionarily conserved and the orthologs of the human THAP genes have been found in mouse, rat, pig, cow, chicken, Xenopus and zebrafish, presumably indicating an important biological role.
disease-causing variants
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THAP12 (aka THAP0, PRKRIR, P52rIPK)
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Paternal variant:
THAP12 (c.829C>A, p.Pro277Thr)
11:76352321 G>T (hg38)
11:76063365 G>T (hg19)
Missense Variant
Maternal variant:
THAP12 (c.312del, p.Glu105AsnfsTer2)
11:76360961 CT>C (hg38)
11:76072005 CT>C (hg19)
Frameshift Variant with loss of function
Clinical presentation due to LOF THAP12
This disease presents primarily as intractable epilepsy starting with Infantile Spasms with hypsarrhythmia before 3 months of age and progressing to more diverse seizure types including Lennox-Gastaut Syndrome.
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Another distinct symptom is severe Hypotonia with known patients unable to gain head control, core control, or weight bearing through limbs.
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Additional global developmental delays are seen as feeding difficulties and dysphagia requiring g-tube dependence, cortical visual impairment, and lack of motor planning preventing purposeful use of limbs
What is thap12?
Available Models
Fibroblast and Lympthoblasts
THAp12 Knockout mouse model
COMING APRIL 2021
from Jackson Labs
Related Research Articles
Topic:
THAP12 as a binding partner to p58ipk (DNAJC3) which is a negative regulator of Protein Kinase R (PKR) activity, and therefore PKR function may be downregulated. Alterations in the PKR pathway may have associations with neurological disorders.
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Topic:
Other THAP Family genes (specifically THAP11) show sensitivity to mutagenesis and association with neurodevelopmental abnormalities.
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