PUBLICATION
Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy
- Authors
- Dominik, N., Efthymiou, S., Record, C.J., Miao, X., Lin, R.Q., Parmar, J.M., Scardamaglia, A., Maroofian, R., Lowe, S.A., Aughey, G.N., Wilson, A.D., Curro, R., Schnekenberg, R.P., Alavi, S., Leclaire, L., He, Y., Zhelcheska, K., Bellaiche, Y., Gaugué, I., Skorupinska, M., Van de Vondel, L., Da'as, S.I., Turchetti, V., Güngör, S., Monahan, G.V., Ghayoor Karimiani, E., Jamshidi, Y., Lamont, P.J., Armirola-Ricaurte, C., Topaloglu, H., Jordanova, A., Zaman, M., Banu, S.H., Marques, W., Tomaselli, P.J., Aynekin, B., Cansu, A., Per, H., Güleç, A., Alvi, J.R., Sultan, T., Khan, A., Zifarelli, G., Ibrahim, S., Mancini, G.M.S., Motazacker, M.M., Brusse, E., Lupo, V., Sevilla, T., Başak, A.N., Tekgul, S., Palvadeau, R.J., Baets, J., Parman, Y., Çakar, A., Horvath, R., Haack, T.B., Stahl, J.H., Grundmann-Hauser, K., Park, J., Zuchner, S., Laing, N.G., Wilson, L.A., Rossor, A.M., Polke, J., Figueiredo, F.B., Pessoa, A., Kok, F., Coimbra-Neto, A.R., Franca, M.C., Ravenscroft, G., Hamed, S.A., Chung, W.K., Pittman, A.M., Osborn, D.P., Hanna, M., Cortese, A., Reilly, M.M., Jepson, J.E., Lamarche-Vane, N., Houlden, H.
- ID
- ZDB-PUB-251015-3
- Date
- 2025
- Source
- The Journal of Clinical Investigation : (Journal)
- Registered Authors
- Da'as, Sahar, Osborn, Dan
- Keywords
- Genetics, Neuromuscular disease, Neuroscience
- MeSH Terms
-
- Alleles*
- Animals
- Charcot-Marie-Tooth Disease*/genetics
- Charcot-Marie-Tooth Disease*/metabolism
- Charcot-Marie-Tooth Disease*/pathology
- Drosophila melanogaster/genetics
- Female
- GTPase-Activating Proteins*/genetics
- GTPase-Activating Proteins*/metabolism
- Humans
- Loss of Function Mutation*
- Male
- Motor Neurons/metabolism
- Motor Neurons/pathology
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- rhoA GTP-Binding Protein/genetics
- rhoA GTP-Binding Protein/metabolism
- PubMed
- 41086021 Full text @ Journal of Clin. Invest.
Citation
Dominik, N., Efthymiou, S., Record, C.J., Miao, X., Lin, R.Q., Parmar, J.M., Scardamaglia, A., Maroofian, R., Lowe, S.A., Aughey, G.N., Wilson, A.D., Curro, R., Schnekenberg, R.P., Alavi, S., Leclaire, L., He, Y., Zhelcheska, K., Bellaiche, Y., Gaugué, I., Skorupinska, M., Van de Vondel, L., Da'as, S.I., Turchetti, V., Güngör, S., Monahan, G.V., Ghayoor Karimiani, E., Jamshidi, Y., Lamont, P.J., Armirola-Ricaurte, C., Topaloglu, H., Jordanova, A., Zaman, M., Banu, S.H., Marques, W., Tomaselli, P.J., Aynekin, B., Cansu, A., Per, H., Güleç, A., Alvi, J.R., Sultan, T., Khan, A., Zifarelli, G., Ibrahim, S., Mancini, G.M.S., Motazacker, M.M., Brusse, E., Lupo, V., Sevilla, T., Başak, A.N., Tekgul, S., Palvadeau, R.J., Baets, J., Parman, Y., Çakar, A., Horvath, R., Haack, T.B., Stahl, J.H., Grundmann-Hauser, K., Park, J., Zuchner, S., Laing, N.G., Wilson, L.A., Rossor, A.M., Polke, J., Figueiredo, F.B., Pessoa, A., Kok, F., Coimbra-Neto, A.R., Franca, M.C., Ravenscroft, G., Hamed, S.A., Chung, W.K., Pittman, A.M., Osborn, D.P., Hanna, M., Cortese, A., Reilly, M.M., Jepson, J.E., Lamarche-Vane, N., Houlden, H. (2025) Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy. The Journal of Clinical Investigation. :.
Abstract
Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Here, we identify 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Combined in vitro and in vivo studies reveal that human ARHGAP19, and conserved ARHGAP19 orthologs in Drosophila and Zebrafish, influence motoneuron morphology and promote locomotor capacity. Transcriptomic studies further demonstrate that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a loss-of-function mechanism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping