Verslag – Rapport – Bericht – Report - GSKE - FMRE

Charcot-Marie-Tooth neuropathies; from genes to protein
networks and disease mechanisms
1. Research report:
In the GSKE project 2011-2013 we aim to implement innovative molecular approaches to find novel
disease causing genes, and develop strategies to study the “not-obvious” Charcot-Marie-Tooth (CMT)
genes. To find functional candidate genes, but also to identify peripheral nerve specific molecular
pathways, we aim to pinpoint differential protein–protein interaction networks. In the project we also
apply novel approaches to model CMT mutations, validate gene function and interaction networks. In
this 2012year report we highlight on our most relevant findings.
In 2012 we reviewed the Hereditary Sensory and Autonomic Neuropathies (HSANs) for Nature Reviews
Neurology (1). This review highlights the key advances in the understanding of HSANs, including
insights into the molecular mechanisms of disease, derived from genetic studies of patients with these
disorders. The HSANs, also known as ulcero-mutilating neuropathies, are a particular group of rare
devastating diseases of the peripheral nervous system characterized by profound sensory loss, acral
mutilations and variable autonomic disturbances. Because of severe mutilations, patients will often have
amputations of their fingers, toes or even limbs. The clinical picture of HSAN disorders impressively
demonstrates the importance of sensory innervations to protect the body from injury. The prevalence
of HSAN is estimated at 1/10.000 and the genetic spectrum encompasses autosomal dominant and
autosomal recessive forms, with 108 causative mutations identified in 13 genes so far. However, the
genetic cause still remains unresolved in at least two-thirds of patients with HSAN. Recently, promising
treatment options for a few genetic subtypes have been demonstrated. A better understanding of the
underlying pathomechanisms, with the final goal to find therapeutic approaches, will improve the quality
of life of patients with inherited but also acquired ulcero-mutilating neuropathies. Research on HSAN will
help to elucidate the mechanisms contributing to long-term neuronal survival, which is not only subject
of rare diseases, but also relevant for common disorders of the ageing society.
We also reviewed the CMT neuropathies and hereditary spastic paraplegias (HSPs) for Experimental
Neurology (2). A key difference between these two groups of conditions is in the target cells that they
primarily affect, with CMT neuropathies affecting the peripheral motor and sensory nerves, while the
HSPs principally affect the central nervous system axons of the corticospinal tract and dorsal columns.
However, CMT neuropathies and HSPs also share many features, for example, both are genetically
determined long axonopathies that affect motor and sensory pathways and which can be later-onset
and are typically progressive. This commonality suggests that there might be similarities in the molecular
pathology underlying these conditions, and in this review manuscript we compared and contrast the
molecular genetics and cellular pathology of the two groups of neurodegenerative diseases. In this
context we recently contributed to an whole exome sequencing (WES) project and identified a REEP1
mutation involved in distal hereditary motor neuropathy type V (distal HMN type V). Our data corroborate
the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies
in REEP1-associated distal HMN type V (3).
We completed in 2012 a study on the use of skin fibroblasts of distal hereditary motor neuropathy
(distal HMN type II) patients, and reported that mutant small heat shock protein HSPB8 causes protein
aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal HMN
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