Two novel missense mutations in FGD4/FRABIN cause Charcot-Marie-Tooth type 4H (CMT4H)

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.

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

Biochemical Society Transactions ◽

10.1042/bst20120197 ◽

2012 ◽

Vol 40 (6) ◽

pp. 1368-1372 ◽

Cited By ~ 18

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.

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Novel compound heterozygous missense mutations in GDAP1 cause Charcot–Marie–Tooth type 4A

Journal of Genetics ◽

10.1007/s12041-021-01307-0 ◽

2021 ◽

Vol 100 (2) ◽

Author(s):

HUIQIN XUE ◽

NEVEN MAKSEMOUS ◽

DAVID SIDHOM ◽

LAN MA ◽

SHAOHUI CHEN ◽

...

Keyword(s):

Compound Heterozygous ◽

Missense Mutations ◽

Charcot Marie Tooth ◽

Tooth Type

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Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Cell Death and Disease ◽

10.1038/s41419-020-02798-y ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 2

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

Abstract Dominantly 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 with 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.

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Faculty Opinions recommendation of Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123373.580534 ◽

2008 ◽

Author(s):

Jun Li ◽

Mario Saporta

Keyword(s):

Mitochondrial Fusion ◽

Mitofusin 2 ◽

Charcot Marie Tooth ◽

Tooth Type ◽

And Function

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Faculty Opinions recommendation of Magnetic resonance neurography and diffusion tensor imaging of the peripheral nerves in patients with Charcot-Marie-Tooth Type 1A.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727611887.793566457 ◽

2019 ◽

Author(s):

Jun Li

Keyword(s):

Diffusion Tensor Imaging ◽

Magnetic Resonance ◽

Peripheral Nerves ◽

Diffusion Tensor ◽

Magnetic Resonance Neurography ◽

Charcot Marie Tooth ◽

Tooth Type ◽

And Diffusion

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

Neurological Sciences ◽

10.1007/s10072-021-05254-7 ◽

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.

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