Molecular basis of Charcot–Marie–Tooth type 2B disease

2012 ◽  
Vol 40 (6) ◽  
pp. 1368-1372 ◽  
Author(s):  
Cecilia Bucci ◽  
Maria De Luca
Keyword(s):  
Small Gtpase ◽  
Effector Proteins ◽  
Endocytic Pathway ◽  
Lower Limbs ◽  
Sensory Loss ◽  
Endosomal Trafficking ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Charcot Marie Tooth ◽  
Tooth Type

CMT2B (Charcot–Marie–Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.

scholarly journals Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1028 ◽  
Author(s):  
Paola Saveri ◽  
Maria De Luca ◽  
Veronica Nisi ◽  
Chiara Pisciotta ◽  
Roberta Romano ◽  
...  
Keyword(s):  
Axonal Neuropathy ◽  
Protein A ◽  
Degradation Process ◽  
Biochemical Properties ◽  
Endocytic Pathway ◽  
Lower Limbs ◽  
Sensory Loss ◽  
Motor Deficits ◽  
Charcot Marie Tooth ◽  
Tooth Type

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.

Rab7 and the CMT2B disease

2009 ◽  
Vol 37 (5) ◽  
pp. 1027-1031 ◽  
Author(s):  
Laura Cogli ◽  
Francesco Piro ◽  
Cecilia Bucci
Keyword(s):  
Molecular Mechanisms ◽  
Axonal Neuropathy ◽  
Endocytic Pathway ◽  
Sensory Loss ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Peripheral Neurons ◽  
Axonal Pathology ◽  
Late Endosomes ◽  
Tooth Type

The CMT2B (Charcot–Marie–Tooth type 2B) disease is an autosomal dominant axonal neuropathy. Sensory loss, distal muscle weakness and wasting, frequent foot ulcers and amputations of the toes due to frequent infections characterize this neuropathy. Four missense mutations in the rab7 gene have been identified as causative of the disease. Rab7 is a small G-protein of the Rab family that controls vesicular transport to late endosomes and lysosomes in the endocytic pathway. The CMT2B-associated mutant Rab7 proteins show altered nucleotide dissociation rates and impaired GTPase activity. In addition, these mutant proteins are predominantly in the GTP-bound form when expressed in human cells and they are able to rescue Rab7 function in Rab7-depleted cells. Thus these mutations generate activated forms of Rab7 that are responsible for the development of the disease. In spite of these results, there are still important gaps in our understanding of the mechanism underlying CMT2B. Indeed, how these mutations in the rab7 gene affect specifically peripheral neurons leading to an axonal pathology in CMT2B is not clear, and it is a particularly puzzling and challenging issue in view of the fact that Rab7 is a ubiquitous protein. The present review discusses possible molecular mechanisms underlying CMT2B.

scholarly journals The impact of symptoms on daily life as perceived by patients with Charcot-Marie-Tooth type 1A disease

2021 ◽  
Author(s):  
Stefano Tozza ◽  
Dario Bruzzese ◽  
Daniele Severi ◽  
Emanuele Spina ◽  
Rosa Iodice ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Daily Life ◽  
Short Form ◽  
Lower Limbs ◽  
Charcot Marie Tooth ◽  
Rank Analysis ◽  
Sf 36 ◽  
Tooth Type ◽  
The Impact

Abstract Introduction In Charcot-Marie-Tooth type 1A (CMT1A) patients, daily life is mainly influenced by mobility and ambulation dysfunctions. The aim of our work was to evaluate the perception of disturbances that mostly impact on daily life in CMT1A patients and its difference on the basis of age, gender, disability, and quality of life. Methods Forty-one CMT1A patients underwent neurological assessment focused on establishing clinical disability through the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and quality of life through the Short Form-36 (SF-36) questionnaire. We identified from CMT disturbances 5 categories [weakness in lower limbs (WLL), weakness in upper limbs (WUL), skeletal deformities (SD), sensory symptoms (SS), balance (B)] and patients classified the categories from the highest to the lowest impact on daily life (1: highest; 5: lowest). Ranking of the 5 categories, in the overall sample and in the different subgroups (dividing by gender, median of age and disease duration, CMTNS, domains of SF-36), was obtained and differences among subgroups were assessed using a bootstrap approach. Results Rank analysis showed that WLL was the most important disturbance on daily life whereas WUL had the lowest impact. In the older CMT1A group, the most important disturbance on daily life was B that was also the most relevant disturbance in patients with a greater disability. SD influenced daily life in younger patients. SS had less impact on daily life, with the exception of patients with a milder disability. Discussion Our findings demonstrated that the perception of disturbances that mostly impact on CMT1A patients’ daily life changes over the lifetime and with degree of disability.

scholarly journals Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway

2009 ◽  
Vol 18 (23) ◽  
pp. 4603-4614 ◽  
Author(s):  
Vincenzo Lupo ◽  
Máximo I. Galindo ◽  
Dolores Martínez-Rubio ◽  
Teresa Sevilla ◽  
Juan J. Vílchez ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Disease Type ◽  
Endocytic Pathway ◽  
Missense Mutations ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

2020 ◽  
Author(s):  
James N. Sleigh ◽  
Aleksandra M. Mech ◽  
Giampietro Schiavo
Keyword(s):  
Housekeeping Gene ◽  
Distinct Pattern ◽  
Missense Mutations ◽  
Wild Type ◽  
Synaptic Growth ◽  
Site Specific ◽  
Charcot Marie Tooth ◽  
Neuromuscular Synapses ◽  
Equivalent Length ◽  
Tooth Type

AbstractDominantly inherited, missense mutations in the widely expressed housekeeping gene, GARS1, cause Charcot-Marie-Tooth type 2D (CMT2D), a peripheral neuropathy characterised by muscle weakness and wasting in limb extremities. Mice modelling CMT2D display early and selective neuromuscular junction (NMJ) pathology, epitomised by disturbed maturation and neurotransmission, leading to denervation. Indeed, the NMJ disruption has been reported in several different muscles; however, a systematic comparison of neuromuscular synapses from distinct body locations has yet to be performed. We therefore analysed NMJ development and degeneration across five different wholemount muscles to identify key synaptic features contributing to the distinct pattern of neurodegeneration in CMT2D mice. Denervation was found to occur along a distal-to-proximal gradient, providing a cellular explanation for the greater weakness observed in mutant Gars hindlimbs compared to forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on site-specific neuromuscular degeneration. Defective NMJ development preceded and associated with degeneration, but was not linked to a delay of wild-type NMJ maturation processes. Correlation analyses indicate that muscle fibre type nor synaptic architecture explain the differential denervation of CMT2D NMJs, rather it is the extent of post-natal synaptic growth that predisposes to neurodegeneration. Together, this work improves our understanding of the mechanisms driving synaptic vulnerability in CMT2D and hints at pertinent pathogenic pathways.

scholarly journals Structure and Dynamics of Mono- vs. Doubly Lipidated Rab5 in Membranes

2019 ◽  
Vol 20 (19) ◽  
pp. 4773 ◽  
Author(s):  
Eileen Münzberg ◽  
Matthias Stein
Keyword(s):  
Bound States ◽  
Cysteine Residue ◽  
Small Gtpase ◽  
Effector Proteins ◽  
Endosomal Trafficking ◽  
Membrane Composition ◽  
Insertion Depth ◽  
Rab Protein ◽  
Guanosine Diphosphate ◽  
C Terminus

The Rab5 small GTPase is a regulator of endosomal trafficking and vesicle fusion. It possesses two adjacent cysteine residues for post-translational geranylgeranylation at its C-terminus for the protein to associate with the early endosome membrane. We compare the effect of mono-lipidification of only one cysteine residue with the doubly modified, fully functional Rab protein in both guanosine diphosphate (GDP)- and guanosine triphosphate (GTP)-bound states and in different membranes (one, three, and six-component membranes). Molecular simulations show that the mono-geranylgeranylated protein is less strongly associated with the membranes and diffuses faster than the doubly lipidated protein. The geranylgeranyl anchor membrane insertion depth is smaller and the protein–membrane distance distribution is broad and uncharacteristic for the membrane composition. The mono-geranylgeranylated protein reveals an unspecific association with the membrane and an orientation at the membrane that does not allow a nucleotide-specific recruitment of further effector proteins. This work shows that double-lipidification is critical for Rab5 to perform its physiological function and mono-geranylgeranylation renders it membrane-associated but non-functional.

scholarly journals Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

2015 ◽  
Vol 35 (14) ◽  
pp. 2464-2478 ◽  
Author(s):  
Wenjing Li ◽  
Hong Zhu ◽  
Xuelian Zhao ◽  
Deborah Brancho ◽  
Yuanxin Liang ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Signal Propagation ◽  
Transforming Growth Factor Β ◽  
Receptor Activation ◽  
Nuclear Accumulation ◽  
Endosomal Trafficking ◽  
Inflammatory Signaling ◽  
Charcot Marie Tooth ◽  
Late Endosomes ◽  
Tooth Type

Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along withendosomalsortingcomplexrequired fortransport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs puncta in late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor β, prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-κB and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.

scholarly journals Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination

2019 ◽  
Author(s):  
Anna E. Mammel ◽  
Katherine C. Delgado ◽  
Andrea L. Chin ◽  
Alec F. Condon ◽  
Jo Q. Hill ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Protein Complexes ◽  
Endosomal Trafficking ◽  
Rab Gtpases ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Type ◽  
Perinatal Lethality ◽  
Radial Sorting ◽  
Redundant Functions

ABSTRACTThe form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET Binding Factor 1; SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Mtmr5 levels were highest during axon radial sorting, whereas Mtmr13 levels rose as myelin formed, and remained high through adulthood. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.

scholarly journals Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Smita Cherry ◽  
Eugene Jennifer Jin ◽  
Mehmet Neset Özel ◽  
Zhiyuan Lu ◽  
Egemen Agi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Protein Function ◽  
Quantitative Imaging ◽  
Small Gtpase ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Mutant Proteins ◽  
Charcot Marie Tooth ◽  
Function Mechanism

The small GTPase Rab7 is a key regulator of endosomal maturation in eukaryotic cells. Mutations in rab7 are thought to cause the dominant neuropathy Charcot-Marie-Tooth 2B (CMT2B) by a gain-of-function mechanism. Here we show that loss of rab7, but not overexpression of rab7 CMT2B mutants, causes adult-onset neurodegeneration in a Drosophila model. All CMT2B mutant proteins retain 10–50% function based on quantitative imaging, electrophysiology, and rescue experiments in sensory and motor neurons in vivo. Consequently, expression of CMT2B mutants at levels between 0.5 and 10-fold their endogenous levels fully rescues the neuropathy-like phenotypes of the rab7 mutant. Live imaging reveals that CMT2B proteins are inefficiently recruited to endosomes, but do not impair endosomal maturation. These findings are not consistent with a gain-of-function mechanism. Instead, they indicate a dosage-dependent sensitivity of neurons to rab7-dependent degradation. Our results suggest a therapeutic approach opposite to the currently proposed reduction of mutant protein function.

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