scholarly journals Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network

2021 ◽  
Vol 22 (2) ◽  
pp. 914
Author(s):  
Katarzyna Binięda ◽  
Weronika Rzepnikowska ◽  
Damian Kolakowski ◽  
Joanna Kaminska ◽  
Andrzej Antoni Szczepankiewicz ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Experimental Therapy ◽  
Negative Effects ◽  
Gene Encoding ◽  
Charcot Marie Tooth Disease ◽  
Terra Incognita ◽  
And Function ◽  
Golgi Network ◽  
Cell Phenotypes ◽  
Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research.

Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a

1993 ◽  
Vol 39 (9) ◽  
pp. 1845-1849 ◽  
Author(s):  
G W Hensels ◽  
E A Janssen ◽  
J E Hoogendijk ◽  
L J Valentijn ◽  
F Baas ◽  
...  
Keyword(s):  
Preliminary Investigation ◽  
Sensory Neuropathy ◽  
Disease Type ◽  
Chromosome 17 ◽  
Hereditary Neuropathy ◽  
Chromosomal Dna ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Abstract Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.

scholarly journals Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

PLoS Genetics ◽  
2010 ◽  
Vol 6 (8) ◽  
pp. e1001081 ◽  
Author(s):  
Duane L. Guernsey ◽  
Haiyan Jiang ◽  
Karen Bedard ◽  
Susan C. Evans ◽  
Meghan Ferguson ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Conformational Maturation and Post-ER Multisubunit Assembly of Gap Junction Proteins

2009 ◽  
Vol 20 (9) ◽  
pp. 2451-2463 ◽  
Author(s):  
Judy K. VanSlyke ◽  
Christian C. Naus ◽  
Linda S. Musil
Keyword(s):  
Gap Junction ◽  
Disulfide Bonds ◽  
Phase Partitioning ◽  
Charcot Marie Tooth Disease ◽  
Human Disorder ◽  
Golgi Network ◽  
Alternative Sites ◽  
Triton X ◽  
Tooth Disease ◽  
Junction Proteins

For all previously well-characterized oligomeric integral membrane proteins, folding, multisubunit assembly, and recognition of conformationally immature molecules for degradation occurs at their organelle of synthesis. This cannot, however, be the case for the gap junction–forming protein connexin43 (Cx43), which when endogenously expressed undergoes multisubunit assembly into connexons only after its transport to the trans-Golgi network. We have developed two novel assays to assess Cx43 folding and assembly: acquisition of resistance of disulfide bonds to reduction by extracellularly added DTT and Triton X-114 detergent phase partitioning. We show that Cx43 synthesized at physiologically relevant levels undergoes a multistep conformational maturation process in which folding of connexin monomers within the ER is a prerequisite for multisubunit assembly in the TGN. Similar results were obtained with Cx32, disproving the widely reported contention that the site of endogenous β connexin assembly is the ER. Exogenous overexpression of Cx43, Cx32, or Cx26 allows these events to take place within the ER, the first example of the TGN and ER as alternative sites for oligomeric assembly. Our findings also constitute the first biochemical evidence that defective connexin folding is a cause of the human disorder X-linked Charcot-Marie-Tooth disease.

scholarly journals Structure of the complete dimeric human GDAP1 core domain provides insights into ligand binding and clustering of disease mutations

2020 ◽  
Author(s):  
Giang Thi Tuyet Nguyen ◽  
Aleksi Sutinen ◽  
Arne Raasakka ◽  
Gopinath Muruganandam ◽  
Remy Loris ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glutathione S Transferase ◽  
Oligomeric State ◽  
Core Domain ◽  
Charcot Marie Tooth Disease ◽  
Disease Mutations ◽  
And Function ◽  
Allosteric Mechanisms ◽  
Gst Family ◽  
Tooth Disease

ABSTRACTCharcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. Despite the common involvement of ganglioside-induced differentiation-associated protein 1 (GDAP1) in CMT, the protein structure and function, as well as the pathogenic mechanisms, remain unclear. We determined the crystal structure of the complete human GDAP1 core domain, which shows a novel mode of dimerization within the glutathione S-transferase (GST) family. The long GDAP1-specific insertion forms an extended helix and a flexible loop. GDAP1 is catalytically inactive towards classical GST substrates. Through metabolite screening, we identified a ligand for GDAP1, the fatty acid hexadecanedioic acid, which is relevant for mitochondrial membrane permeability and Ca2+ homeostasis. The fatty acid binds to a pocket next to a CMT-linked residue cluster, increases protein stability, and induces changes in protein conformation and oligomerization. The closest homologue of GDAP1, GDAP1L1, is monomeric in its full-length form. Our results highlight the uniqueness of GDAP1 within the GST family and point towards allosteric mechanisms in regulating GDAP1 oligomeric state and function.

scholarly journals Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice

2019 ◽  
Author(s):  
Ji-Su Lee ◽  
Jae Y Lee ◽  
Dong W Song ◽  
Hee S Bae ◽  
Hyun M Doo ◽  
...  
Keyword(s):  
Tata Box ◽  
Chromosome 17 ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Inherited Neuropathy ◽  
Its Gene ◽  
Multiple Copies ◽  
Human Chromosome 17 ◽  
Tooth Disease

Abstract Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A.

scholarly journals Atypical presentation of Charcot-Marie-Tooth disease type 1C with a new mutation: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Monika Turčanová Koprušáková ◽  
Milan Grofik ◽  
Ema Kantorová ◽  
Petra Jungová ◽  
Ján Chandoga ◽  
...  
Keyword(s):  
New Mutation ◽  
Gene Encoding ◽  
Case Presentation ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Inflammatory Neuropathy ◽  
Inherited Neuropathies ◽  
Partial Effects ◽  
Progressive Weakness ◽  
Tooth Disease

Abstract Background Charcot-Marie-Tooth 1C (CMT1C) is a rare form of dominantly inherited CMT1 neuropathy caused by a mutated gene encoding lipopolysaccharide-induced tumour necrosis alpha factor (LITAF). Case presentation We report a 56-year-old patient with an atypical clinical phenotype of CMT1C, which started as progressive weakness of a single upper limb resembling acquired inflammatory neuropathy. Nerve conduction studies (NCS) and temporarily limited and partial effects of immunotherapy supported the diagnosis of inflammatory neuropathy. Significant progression of polyneuropathy, despite intensive long-lasting immunotherapy, together with repeatedly negative auxiliary investigations (CSF, MRI and antibodies) and genetic testing results finally led to the diagnosis of CMT1C neuropathy. Conclusions CMT1C should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy.

scholarly journals KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth

2018 ◽  
Vol 217 (10) ◽  
pp. 3480-3496 ◽  
Author(s):  
Fang Xu ◽  
Hironori Takahashi ◽  
Yosuke Tanaka ◽  
Sotaro Ichinose ◽  
Shinsuke Niwa ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Binding Capacity ◽  
Axon Growth ◽  
Hereditary Neuropathy ◽  
Binding Partner ◽  
Charcot Marie Tooth Disease ◽  
Direct Binding ◽  
And Function ◽  
Igf1r Expression ◽  
Tooth Disease

KIF1Bβ is a kinesin-3 family anterograde motor protein essential for neuronal development, viability, and function. KIF1Bβ mutations have previously been reported in a limited number of pedigrees of Charcot-Marie-Tooth disease type 2A (CMT2A) neuropathy. However, the gene responsible for CMT2A is still controversial, and the mechanism of pathogenesis remains elusive. In this study, we show that the receptor tyrosine kinase IGF1R is a new direct binding partner of KIF1Bβ, and its binding and transport is specifically impaired by the Y1087C mutation of KIF1Bβ, which we detected in hereditary neuropathic patients. The axonal outgrowth and IGF-I signaling of Kif1b−/− neurons were significantly impaired, consistent with decreased surface IGF1R expression. The complementary capacity of KIF1Bβ-Y1087C of these phenotypes was significantly impaired, but the binding capacity to synaptic vesicle precursors was not affected. These data have supported the relevance of KIF1Bβ in IGF1R transport, which may give new clue to the neuropathic pathogenesis.

scholarly journals Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations

2021 ◽  
Vol 7 ◽  
Author(s):  
Giang Thi Tuyet Nguyen ◽  
Aleksi Sutinen ◽  
Arne Raasakka ◽  
Gopinath Muruganandam ◽  
Remy Loris ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glutathione S Transferase ◽  
Oligomeric State ◽  
Core Domain ◽  
Charcot Marie Tooth Disease ◽  
Disease Mutations ◽  
And Function ◽  
Allosteric Mechanisms ◽  
Gst Family ◽  
Tooth Disease

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. Despite the common involvement of ganglioside-induced differentiation-associated protein 1 (GDAP1) in CMT, the protein structure and function, as well as the pathogenic mechanisms, remain unclear. We determined the crystal structure of the complete human GDAP1 core domain, which shows a novel mode of dimerization within the glutathione S-transferase (GST) family. The long GDAP1-specific insertion forms an extended helix and a flexible loop. GDAP1 is catalytically inactive toward classical GST substrates. Through metabolite screening, we identified a ligand for GDAP1, the fatty acid hexadecanedioic acid, which is relevant for mitochondrial membrane permeability and Ca2+ homeostasis. The fatty acid binds to a pocket next to a CMT-linked residue cluster, increases protein stability, and induces changes in protein conformation and oligomerization. The closest homologue of GDAP1, GDAP1L1, is monomeric in its full-length form. Our results highlight the uniqueness of GDAP1 within the GST family and point toward allosteric mechanisms in regulating GDAP1 oligomeric state and function.

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