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.

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

THAP12 (aka THAP0, PRKRIR, P52rIPK)

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.

Another distinct symptom is severe Hypotonia with known patients unable to gain head control, core control, or weight bearing through limbs. 

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?

 
 
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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.

Regulation of Interferon-Induced Protein Kinase PKR: Modulation of P58IPK Inhibitory Function by a Novel Protein, P52rIPK

Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition

Topic:

Other THAP Family genes (specifically THAP11) show sensitivity to mutagenesis and association with neurodevelopmental abnormalities.

THAP11F80L cobalamin disorder-associated mutation reveals normal and pathogenic THAP11 functions in gene expression and cell proliferation

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