My Research

By studying inherited metabolic disorders, we hope to speed up diagnosis and develop treatments for affected patients. However, we can also acquire exciting fundamental scientific insights into metabolic pathways and mechanisms. An example of this is in our study of a newly identified CDG caused by pathogenic variants in DHRSX. Through the identification of affected patients, we were able to revise the metabolism of dolichol to include three additional steps and two new metabolites, with profound implications for its regulation and organization. Dolichol is critically important for several glycosylation pathways, so changing our understanding of this pathway has also led us to rethink how early glycosylation may be regulated. We have subsequently shown that this revised dolichol synthesis pathway is intact in all mammals, and upcoming (unpublished) work will extend this to all Eukaryotes. We are starting to realise the implications of this for both rare diseases, wider glycosylation pathways, and lipid metabolism more generally (watch this space!)

• Wilson, M.P., Morava, E. (2025). Dolichol synthesis defects: a cautionary note on the use of statins. Mol Genet Metab, 145 (4). doi: 10.1016/j.ymgme.2025.109186

• Kentache, T., Althoff, C.R., Caligiore, F., Souche, E., Schulz, C., Graff, J., Pieters, E., Stanley, P., Contessa, J.N., Van Schaftingen, E., Matthijs, G., Foulquier, F., Bommer, G.T., Wilson, M.P.  (2024). Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells. JOURNAL OF BIOLOGICAL CHEMISTRY, 300 (12), Art.No. ARTN 107875. doi: 10.1016/j.jbc.2024.107875

• Wilson, M.P.*, Kentache, T.*, Althoff, C.R.*, Schulz, C., de Bettignies, G., Cabrera, G.M., Cimbalistiene, L., Burnyte, B., Yoon, G., Costain, G., Vuillaumier-Barrot, S., Cheillan, D., Rymen, D., Rychtarova, L., Hansikova, H., Bury, M., Dewulf, J.P., Caligiore, F., Jaeken, J., Cantagrel, V., Van Schaftingen, E., Matthijs, G., Foulquier, F., Bommer, G.T. with Van Schaftingen, E. (corresp. author), Matthijs, G. (corresp. author), Foulquier, F. (corresp. author), Bommer, G.T. (corresp. author) (2024). A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis. CELL, 187 (14). doi: 10.1016/j.cell.2024.04.041

Congenital Disorders of Glycosylation are a group of approximately 200 rare inherited metabolic disorders caused by gene defects leading to defective glycosylation of proteins or lipids. CDG are complex, and treatments are mostly elusive, meaning the characterization of their underlying mecahnisms is important for the development of therapies in the future. Using next generation sequencing techniques we have made several contributions to CDG over the past few years. This includes identification of one of the first dominantly-inherited CDG, AD STT3A-CDG, which leads to disorder of variable severity and has a fascinating mechanism whereby pathogenic missense variants are found exclusively at the active site. We also identified CAMLG-CDG, with a complex mechanism consisting of the abnormal insertion of tail-anchored proteins into the ER membrane, some of which are subsequently important for 

 glycosylation pathways. Finally, our most impactful discovery in recent years was that of DHRSX-CDG, which led us to revise the dolichol metabolism pathway, as described above.

• Raynor A., de Sainte-Agathe J-M., Post M.A., Barth M., Zijlstra F., Huijben K., Kouri I., Couasnard A., Bellenda P., Dupré T., Souche E., Lebredonchel E., Cholet S., Cantaloube I., Ratier A., Jacquin E., Peoc’h K.,  Fenaille F., Matthijs G., Jaeken J., Bandeira A., Quelhas D., Lefeber D.J., Bruneel A., Wilson M.P. ATP6AP2-Related Disease Caused by Splicing Defects: Abnormal Glycosylation and the First Affected Female,” Journal of Inherited Metabolic Disease 48, no. 6 (2025): e70109,  https://doi.org/10.1002/jimd.70109.

• Wilson, M.P.*, Kentache, T.*, Althoff, C.R.*, Schulz, C., de Bettignies, G., Cabrera, G.M., Cimbalistiene, L., Burnyte, B., Yoon, G., Costain, G., Vuillaumier-Barrot, S., Cheillan, D., Rymen, D., Rychtarova, L., Hansikova, H., Bury, M., Dewulf, J.P., Caligiore, F., Jaeken, J., Cantagrel, V., Van Schaftingen, E., Matthijs, G., Foulquier, F., Bommer, G.T. with Van Schaftingen, E. (corresp. author), Matthijs, G. (corresp. author), Foulquier, F. (corresp. author), Bommer, G.T. (corresp. author) (2024). A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis. CELL, 187 (14). doi: 10.1016/j.cell.2024.04.041

• Wilson, M.P., Durin, Z., Unal, O., Ng, B.G., Marrecau, T., Keldermans, L., Souche, E., Rymen, D., Gunduz, M., Kose, G., Sturiale, L., Garozzo, D., Freeze, H.H., Jaeken, J., Foulquier, F., Matthijs, G. (2022). CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking. HUMAN MOLECULAR GENETICS, 31 (15), 2571-2581. doi: 10.1093/hmg/ddac055

• Wilson, M.P., Garanto, A., Vairo, F.P E., Ng, B.G., Ranatunga, W.K., Ventouratou, M., Baerenfaenger, M., Huijben, K., Thiel, C., Ashikov, A., Keldermans, L., Souche, E., Vuillaumier-Barrot, S., Dupre, T., Michelakakis, H., Fiumara, A., Pitt, J., White, S.M., Lim, S.C., Gallacher, L., Peters, H., Rymen, D., Witters, P., Ribes, A., Morales-Romero, B., Rodriguez-Palmero, A., Ballhausen, D., de Lonlay, P., Barone, R., Janssen, M.C H., Jaeken, J., Freeze, H.H., Matthijs, G., Morava, E., Lefeber, D.J. with Wilson, M.P. (corresp. author), Lefeber, D.J. (corresp. author) (2021). Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings. AMERICAN JOURNAL OF HUMAN GENETICS, 108 (11), 2130-2144. doi: 10.1016/j.ajhg.2021.09.012

• Wilson, M.P., Quelhas, D., Leão-Teles, E., Sturiale, L., Rymen, D., Keldermans, L., Race, V., Souche, E., Rodrigues, E., Campos, T., Van Schaftingen, E., Foulquier, F., Garozzo, D., Matthijs, G., Jaeken, J. (2021). SLC37A4-CDG: Second patient. JIMD Reports, 58 (1), 122-128. doi: 10.1002/jmd2.12195

Rare genetic disorders leading to deficiencies in enzymes important for the metabolism or trafficking of Vitamin B6 lead to a seizure disorder accompanied by developmental or intellectual disabilities. However, prompt and correct treatment of these disorders can lead to a normal neurodevelopmental outcome. During my PhD we identified PROSC mutations as a novel cause of vitamin B6-dependent epilepsy, which led to the renaming of PROSC to PLPHP (Pyridoxal 5'-phosphate homeostasis protein) and the discovery of a new role for this protein: the chaperoning of active vitamin B6. Later on, we discovered that missense variants in PDXK, encoding the pyridoxal kinase protein, led to a novel traetable polyneuropathy caused by vitamin B6 deficiency.

• Darin, N., Reid, E., Prunetti, L., Samuelsson, L., Husain, R.A., Wilson, M., El Yacoubi, B., Footitt, E., Chong, W.K., Wilson, L.C., Prunty, H., Pope, S., Heales, S., Lascelles, K., Champion, M., Wassmer, E., Veggiotti, P., de Crecy-Lagard, V., Mills, P.B., Clayton, P.T. (2016). Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy. AMERICAN JOURNAL OF HUMAN GENETICS, 99 (6), 1325-1337. doi: 10.1016/j.ajhg.2016.10.011

• Chelban, V., Wilson, M.P., Chardon, J.W., Vandrovcova, J., Zanetti, M.N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M.R., Abis, G., Liu, Y-T., Tribollet, E., Haridy, N.A., Botia, J.A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K.D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J.E C., Bello, O., Bremner, F., Cordivari, C., Reilly, M.M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S.J R., Wood, N.W., Rothman, J.E., Boycott, K.M., Mills, P.B., Clayton, P.T., Houlden, H. (2019). PDXK mutations cause polyneuropathy responsive to pyridoxal 5 '-phosphate supplementation. ANNALS OF NEUROLOGY, 86 (2), 225-240. doi: 10.1002/ana.25524

Vitamin B6-dependent seizure disorders are usually treatable with high doses of specific subtypes of vitamin B6. However, this is dependent on rapid diagnosis and selection of the correct treatment. We made contributions by developing a rapid mass spectrometry-based method for the diagnosis of PNPO deficiency from dried blood spots and assessing the quality of Pyridoxal 5'-Phosphate preparations used for treatment, as well as advising a treatment plan for these patients. Finally, our work on dried blood spots was eventually extended to another mass spectrometry-based dried blood spot method for ALDH7A1 deficiency.

Khalil, Y., Footitt, E., Vootukuri, R., Wempe, M.F., Coughlin, C.R., Batzios, S., Wilson, M.P., Kozich, V., Clayton, P.T., Mills, P.B. with Mills, P.B. (corresp. author) (2025). Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency. JOURNAL OF INHERITED METABOLIC DISEASE, 48 (1). doi: 10.1002/jimd.12783

Wilson, M.P., Footitt, E.J., Papandreou, A., Uudeleppt, M-L., Pressler, R., Stevenson, D.C., Gabriel, C., McSweeney, M., Baggot, M., Burke, D., Stodberg, T., Riney, K., Schiff, M., Heales, S.J R., Mills, K.A., Gissen, P., Clayton, P.T., Mills, P.B. (2017). An LC-MS/MS-Based Method for the Quantification of Pyridox(am)ine 5′-Phosphate Oxidase Activity in Dried Blood Spots from Patients with Epilepsy. ANALYTICAL CHEMISTRY, 89 (17), 8892-8900. doi: 10.1021/acs.analchem.7b01358

Mohamed-Ahmed, A.H A.*, Wilson, M.P.*, Albuera, M., Chen, T., Mills, P.B., Footitt, E.J., Clayton, P.T., Tuleu, C. (2017). Quality and stability of extemporaneous pyridoxal phosphate preparations used in the treatment of paediatric epilepsy. JOURNAL OF PHARMACY AND PHARMACOLOGY, 69 (4), 480-488. doi: 10.1111/jphp.12701 *Joint first authors