Targeted exomes reveal simultaneous <i><scp>MFN</scp>2</i> and <i><scp>GDAP</scp>1</i> mutations in a severe Charcot‐Marie‐Tooth disease type 2 phenotype

Anghelescu, Cristina; Francou, Bruno; Cardas, Ruxandra; Guiochon‐Mantel, Anne; Aubourg, Patrick; Servais, Laurent; Gidaro, T.

doi:10.1111/ene.13250

Cited by 6 publications

(5 citation statements)

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“…Therefore, we proposed a coordinated role of GDAP1 and MFN2 regulating MCSs with other organelles. Of note, in agreement with our proposal, it has been reported the rare coinheritance of GDAP1 and MFN2 pathogenic variants is associated with an accumulative effect on the observed phenotype ( Kostera-Pruszczyk et al, 2014 ; Anghelescu et al, 2017 ). Indeed, it has been described the digenic inheritance in patients carrying mutations in both genes ( Barreda Fierro et al, 2020 ).…”

Section: Discussionsupporting

confidence: 93%

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases

et al. 2022

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Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients’ fibroblasts except for CHKBQ198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1W67L/W67L, DRP1K75E/+, OPA1F570L/+, and FXNR165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1W67L/W67L exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2R104W/+ fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1W67L/W67L and MFN2R104W/+ fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria–lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1K75E/+, GDAP1W67L/W67L, OPA1F570L/+, MFN2R104W/+, and CHKBQ198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

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Section: Discussionsupporting

confidence: 93%

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases

et al. 2022

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“…A population study of 787 patients with CMT identified at least 11 patients with multiple CMT subtypes (CMT1A/1E, CMT1E/1B, CMTX1/1B or CMT1A/1C), and as not all patients were tested for multiple variants, this percentage could be higher 11 . Other examples include the coexistence of the 17p duplication with two LITAF variants in a patient with severe CMT1 74 , and the presence of both MFN2 and GDAP1 variants in a patient with severe CMT2 75 . Furthermore, a recent retrospective analysis of 2,076 patients with a rare genetic diagnosis found that that 5% of patients had between two and four diagnoses 76 , suggesting that the cooccurrence of more than one independent genetic diagnosis in a single individual is more common than previously thought.…”

Section: Phenotype-genotype Associationsmentioning

confidence: 99%

Next-generation sequencing in Charcot–Marie–Tooth disease: opportunities and challenges

2019

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Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine, and as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing (WES), wholegenome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify 2 structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

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“…Recently, a Japanese cohort study identified 5 out of 1,005 families with CMT harboring coinherited variants, accounting for 0.5% (5/1,005) of the total, in which the "double trouble" effect of concomitant variants were the underlying causes (32). Compared with the "genetic modifier" effect of GDAP1 variants observed in this study, the coexistence of homozygous AR-CMT2K (p.Q163X) or heterozygous autosomal dominant-CMT2K (p.H123R, p.E222K, and p.R120W) variant in GDAP1 and heterozygous variant in MFN2 had been reported associating with a more severe phenotype, suggesting the "double trouble" effect of concomitant MFN2 and GDAP1 variants (28,30,33,34). Moreover, concomitant variants were also related to true digenic inheritance (DI) that has been defined as the coinheritance of two nonallelic mutations, both are indispensable to establish the diagnosis (35).…”

Section: Discussionmentioning

confidence: 45%

One PMP22/MPZ and Three MFN2/GDAP1 Concomitant Variants Occurred in a Cohort of 189 Chinese Charcot-Marie-Tooth Families

Xie

Lin

et al. 2022

Front. Neurol.

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Background and AimsCharcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. The wide phenotypic variability may not be completely explained by a single mutation.Aims and MethodsTo explore the existence of concomitant variants in CMT, we enrolled 189 patients and performed molecular diagnosis by application of next-generation sequencing combined with multiplex ligation-dependent probe amplification. We conducted a retrospective analysis of patients harboring coinherited variants in different genes.ResultsFour families were confirmed to possess variants in two genes, accounting for 2.1% (4/189) of the total in our cohort. One CMT1 patient with PMP22 duplication and MPZ variant (c.286A>C, p.K96Q) exhibited moderate neuropathy with infantile onset, while her father possessing MPZ variant was mildly affected with adolescence onset. A CMT2 patient with heterozygous variants in MFN2 (c.613_622delGTCACCACAG, p.V205Sfs*26) and GDAP1 (c.713G>T, p.W238L) exhibited childhood onset mild phenotype, while his mother with MFN2 variant developed bilateral pes cavus only. A CMT2 patient with heterozygous variants in MFN2 (c.839G>A, p.R280H) and GDAP1 (c.3G>T, p.M1?) presented infantile onset and rapid progression, while her father with MFN2 variant presented with absence of deep tendon reflexes. One sporadic CMT2 patient with early onset was confirmed harboring de novo MFN2 variant (c.1835C>T, p.S612F) and heterozygous GDAP1 variant (c.767A>G, p.H256R).ConclusionOur results suggest that the possibility of concomitant variants was not uncommon and should be considered when significant intrafamilial clinical heterogeneity is observed.

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Targeted exomes reveal simultaneous MFN2 and GDAP1 mutations in a severe Charcot‐Marie‐Tooth disease type 2 phenotype

Cited by 6 publications

References 5 publications

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases

Next-generation sequencing in Charcot–Marie–Tooth disease: opportunities and challenges

One PMP22/MPZ and Three MFN2/GDAP1 Concomitant Variants Occurred in a Cohort of 189 Chinese Charcot-Marie-Tooth Families

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