SUMMARY:
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.
TITLE:
Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1
DESCRIPTION:
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…
CONTENT:
FEBS Open Bio. 2022 May 4. doi: 10.1002/2211-5463.13422. Online ahead of print.
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 significant 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.
PMID:35509130 | DOI:10.1002/2211-5463.13422
SOURCE:
FEBS open bio
TAGS:
GDAP1
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-05-05T04:37:32Z
DATE – DOI: 2022-05-05T04:37:32Z
DATE – PUBMED: 2022 May 4
DATE OUTPUT MATCHED: True
DATE – ADDED:
Thu, 05 May 2022 06:00:00 -0400
DATE – RETRIEVED:
05/05/22 07:18AM
2022-05-05T07:18:13-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:35509130,doi:10.1002/2211-5463.13422
PUBMED ID:
pubmed:35509130
DOI:
10.1002/2211-5463.13422
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35509130/
LINK – DOI:
https://doi.org/10.1002/2211-5463.13422
LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/2211-5463.13422
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-05T07:18:13-04:00, https://www.cmttreatmentreport.com.