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Research Projects

Lightning and Love Foundation is the sole driver of research of THAP12 Genetic Disease, bringing together scientists, clinicians and companies to ensure this condition is making progress towards a CURE

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University of Montreal 

Partnership with the Samarut Lab 

Our partnership with the Eric Samarut Lab @ University of Montreal began with a simple first-generation THAP12 CRISPR knockout Zebrafish model. This model showed seizure-like behaviors and abnormal brain MRI. This strong evidence led to Lightning and Love Foundation sponsoring a stable Zebrafish line and a humanized mouse model. The lab was also granted Catalyst funding from the Rare Disease Model and Mechanisms Network for research of the novel THAP12 gene and its function in rare disease. The ongoing partnership between the Samarut Lab and the Lightning and Love Foundation aims at publishing the very first THAP12 research papers and driving the fundamental scienfiic learning needed for drug discovery for this devestating disease. 

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A Public Benefit Corporation Partnership

Rarebase Collaboration

Lightning and Love Foundation is excited to partner with Rarebase and to leverage their network of expert scientists, specialist laboratories, and leading biotechnology companies as they evaluate all feasible therapeutic approaches in parallel. We trust they will prioritize technologies that can be rapidly translated to clinical settings and help our organization move steadily towards a disease treatment. 

International Mouse Phenotyping Consortium in partnership with Jackson Labs

Knockout Mouse Model @ Jackson Labs

The NIH Funded Knockout Mouse Program through the International Mouse Phenotyping Consortium generated the first THAP12 Knockout Mouse Model. The intercross of germline confirmed mice showed no homozygotes, indicating likely embryonic lethal line. The project is continuing with the heterozygous animals going through the Knockout Mouse Project phenotyping pipeline for a range of clinical assessments, and the mutant embryos being evaluated for time of death and phenotype at that time. 

Coriell Institute for Medical Research

NIGMS Cell Repository

The NIGMS Human Genetic Cell Repository, sponsored by the National Institute of General Medical Sciences, provides scientists around the world with resources for cell and genetic research. THAP12 Cell lines are currently available for research through Coriell and can be ordered here.

 
 
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Available Models

Fibroblasts and Lymphoblasts 

through Coriell Institute NIGMS Repository

THAP12 Knockout Mouse model through Jackson Labs for the International Mouse Phenotyping Consortium

 

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 of THAP12 Disease

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

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

Information For Scientists and Researchers

Join our Team

We are proud advocates of open science and collaboration. If you like the idea of contributing to research of an orphan disease and growing the understanding of a newly discovered pathogenetic gene, THAP12, please reach out! We would love to talk with you!