Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Sutinen, A.; Nguyen, G. T. T.; Raasakka, A.; Muruganandam, G.; Loris, R.; Ylikallio, E.; Tyynismaa, H.; Bartesaghi, L.; Ruskamo, S.; Kursula, P.

doi:10.1101/2022.02.18.481076

bioRxiv · 10.1101/2022.02.18.481076

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Sutinen, A.·Nguyen, G. T. T.·Raasakka, A.·Muruganandam, G.·Loris, R.·Ylikallio, E.·Tyynismaa, H.·Bartesaghi, L.·Ruskamo, S.·Kursula, P.

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Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R as well as CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behaviour, but both present a large decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side chain interaction network between helices 3, 6, and 7, which is affected by CMT mutations, as well as a hinge in the long helix 6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

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Sutinen, A., Nguyen, G. T. T., Raasakka, A., Muruganandam, G., Loris, R., Ylikallio, E., Tyynismaa, H., Bartesaghi, L., Ruskamo, S., Kursula, P.. 2022-02-18. Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1. https://doi.org/10.1101/2022.02.18.481076

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