Nhlrc1-KO Mouse

NHLRC1, encoding an ubiquitin ligase, is associated with Lafora disease in both humans and dogs when mutated [7]. In humans, mutations in either EPM2A or NHLRC1 lead to Lafora disease, characterized by the accumulation of polyglucosan bodies in neurons and progressive neurological signs like myoclonic epilepsy [1,6,7]. The gene is also involved in DNA methylation-related processes in lung cancer. Hypomethylation in a region near NHLRC1 increases its mRNA transcription in lung tumors, and its knockdown in lung cancer cells affects cell proliferation, viability, migration, invasion, and AKT phosphorylation [4].

In dogs, a dodecamer expansion in NHLRC1 has been identified as the cause of Lafora disease in multiple breeds including miniature wire-haired Dachshunds, Basset Hounds, Beagles, Chihuahuas, Pembroke Welsh Corgis, and a Newfoundland dog [1,2,3,5]. This mutation has been the only known Lafora disease genetic variant in dogs so far [5]. In Turkey, the rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease [6]. Also, patients with NHLRC1 mutations in Lafora disease seem to have a slower disease progression compared to those with EPM2A mutations [8].

In conclusion, NHLRC1 is crucial in preventing Lafora disease, both in humans and dogs. Mutations in this gene lead to the characteristic symptoms of the disease. In addition, its role in DNA methylation-related lung cancer processes shows its importance in other disease contexts. The study of NHLRC1 in these genetic models helps understand the disease mechanisms and may potentially lead to new treatment strategies for Lafora disease and lung cancer.

References:

1. Mari, L, Comero, G, Mueller, E, Kuehnlein, P, Kehl, A. 2021. NHLRC1 homozygous dodecamer expansion in a Newfoundland dog with Lafora disease. In The Journal of small animal practice, 62, 1030-1032. doi:10.1111/jsap.13396. https://pubmed.ncbi.nlm.nih.gov/34263924/

2. Kehl, Alexandra, Cizinauskas, Sigitas, Langbein-Detsch, Ines, Mueller, Elisabeth. 2019. NHLRC1 dodecamer expansion in a Welsh Corgi (Pembroke) with Lafora disease. In Animal genetics, 50, 413-414. doi:10.1111/age.12795. https://pubmed.ncbi.nlm.nih.gov/31172540/

3. Barrientos, Laura, Maiolini, Arianna, Häni, Annakatrin, Jagannathan, Vidhya, Leeb, Tosso. 2018. NHLRC1 dodecamer repeat expansion demonstrated by whole genome sequencing in a Chihuahua with Lafora disease. In Animal genetics, 50, 118-119. doi:10.1111/age.12756. https://pubmed.ncbi.nlm.nih.gov/30525203/

4. Faltus, Christian, Lahnsteiner, Angelika, Barrdahl, Myrto, Kaaks, Rudolf, Risch, Angela. 2022. Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS). In International journal of molecular sciences, 23, . doi:10.3390/ijms231810699. https://pubmed.ncbi.nlm.nih.gov/36142605/

5. Hajek, I, Kettner, F, Simerdova, V, Minassian, B A, Palus, V. 2016. NHLRC1 repeat expansion in two beagles with Lafora disease. In The Journal of small animal practice, 57, 650-652. doi:10.1111/jsap.12593. https://pubmed.ncbi.nlm.nih.gov/27747878/

6. Haryanyan, Garen, Ozdemir, Ozkan, Tutkavul, Kemal, Ugur Iseri, Sibel A, Bebek, Nerses. 2021. The rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease in Turkey. In Journal of human genetics, 66, 1145-1151. doi:10.1038/s10038-021-00944-8. https://pubmed.ncbi.nlm.nih.gov/34117373/

7. Singh, Shweta, Ganesh, Subramaniam. . Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. In Human mutation, 30, 715-23. doi:10.1002/humu.20954. https://pubmed.ncbi.nlm.nih.gov/19267391/

8. Singh, S, Sethi, I, Francheschetti, S, Delgado-Escueta, A V, Ganesh, S. . Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. In Journal of medical genetics, 43, e48. doi:. https://pubmed.ncbi.nlm.nih.gov/16950819/