FASTKD2, also known as KIAA0971, is a mitochondrial RNA-binding protein. It is essential for mitochondrial RNA processing and translation, playing a key role in the synthesis of components of the electron transport chain. It is involved in pathways related to oxidative phosphorylation (OXPHOS), which is crucial for ATP production in cells [4,5].

Mutations in FASTKD2 have been associated with multiple diseases. In two siblings, a FASTKD2 mutation was found in cases presenting with status epilepticus, initially misdiagnosed as metabolic and viral encephalitis [1]. In pancreatic ductal adenocarcinoma, dysregulation of FASTKD2 led to poor prognosis, as it promoted cancer cell proliferation and invasion through upregulating Myc expression [2]. Three novel FASTKD2 mutations were identified in patients with mitochondrial encephalomyopathy, causing multi-OXPHOS deficiency, and zebrafish knockdown models showed similar mitochondrial function impairment [3]. A homozygous missense mutation in FASTKD2 was associated with Lennox-Gastaut syndrome, with lower expression of FASTKD2 and mitochondrial 16S rRNA levels in the patient [6]. A new homozygous loss-of-function variant in FASTKD2 was reported in an adolescent with new-onset refractory status epilepticus, and the phenotypical spectrum of FASTKD2-related mitochondrial disease is heterogeneous [7].

In conclusion, FASTKD2 is vital for mitochondrial RNA processing and translation, with its dysfunction leading to various diseases such as mitochondrial encephalomyopathy, epilepsy-related syndromes, and pancreatic cancer. Studies using model organisms like zebrafish have been valuable in understanding the role of FASTKD2 in these disease conditions, helping to uncover its biological functions and potential as a therapeutic target.

References:

1. Shah, Ritesh, Balasubramaniam, Seema. 2021. Clinical Phenotype of FASTKD2 Mutation. In Journal of pediatric neurosciences, 16, 319-322. doi:10.4103/jpn.JPN_199_20. https://pubmed.ncbi.nlm.nih.gov/36531759/

2. Fang, Rui, Zhang, Bin, Lu, Xiaoming, Jin, Xin, Liu, Tao. 2019. FASTKD2 promotes cancer cell progression through upregulating Myc expression in pancreatic ductal adenocarcinoma. In Journal of cellular biochemistry, 121, 2458-2466. doi:10.1002/jcb.29468. https://pubmed.ncbi.nlm.nih.gov/31692063/

3. Wei, Xiujuan, Du, Miaomiao, Li, Dongxiao, Yang, Yanling, Fang, Hezhi. 2020. Mutations in FASTKD2 are associated with mitochondrial disease with multi-OXPHOS deficiency. In Human mutation, 41, 961-972. doi:10.1002/humu.23985. https://pubmed.ncbi.nlm.nih.gov/31944455/

4. Popow, Johannes, Alleaume, Anne-Marie, Curk, Tomaz, Sauer, Sven, Hentze, Matthias W. 2015. FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. In RNA (New York, N.Y.), 21, 1873-84. doi:10.1261/rna.052365.115. https://pubmed.ncbi.nlm.nih.gov/26370583/

5. Arroyo, Jason D, Jourdain, Alexis A, Calvo, Sarah E, Root, David E, Mootha, Vamsi K. 2016. A Genome-wide CRISPR Death Screen Identifies Genes Essential for Oxidative Phosphorylation. In Cell metabolism, 24, 875-885. doi:10.1016/j.cmet.2016.08.017. https://pubmed.ncbi.nlm.nih.gov/27667664/

6. Wu, Tenghui, Mao, Leilei, Chen, Chen, Yin, Fei, Peng, Jing. 2022. A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome. In Journal of human genetics, 67, 589-594. doi:10.1038/s10038-022-01056-7. https://pubmed.ncbi.nlm.nih.gov/35729327/

7. Astner-Rohracher, Alexandra, Mauritz, Matthias, Leitinger, Markus, Mayr, Johannes A, Trinka, Eugen. 2023. A case report: New-onset refractory status epilepticus in a patient with FASTKD2-related mitochondrial disease. In Frontiers in neurology, 13, 1063733. doi:10.3389/fneur.2022.1063733. https://pubmed.ncbi.nlm.nih.gov/36712458/