Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

Schon, Katherine; Spasić-Bošković, Olivera; Brügger, Kim; Graves, Tracey D.; Abbs, Stephen; Park, Soo‐Mi; Ambegaonkar, Gautam; Armstrong, Ruth

doi:10.1007/s10048-016-0504-2

Cited by 6 publications

(5 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mosaicism has been previously reported in other forms of CMT. The clinical manifestation of mosaic status was always present later onset and milder form of the disease, including asymptomatic with normal neurophysiology (Borgulová et al, ; McLaughlin et al, ; Schon et al, ; Spinner & Conlin, ). Hence, the proband's mother was most likely to be explained by the somatic mosaicism.…”

Section: Discussionmentioning

confidence: 99%

ATP1A1mutations cause intermediate Charcot‐Marie‐Tooth disease

Guo

Lin

et al. 2019

Human Mutation

View full text Add to dashboard Cite

Intermediate Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using wholeexome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families.Further functional analysis revealed that these mutations led to the loss function of the ATP1A1 protein. The two mutations did not affect the levels of messenger RNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation.Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT.

show abstract

Section: Discussionmentioning

confidence: 99%

ATP1A1mutations cause intermediate Charcot‐Marie‐Tooth disease

Guo

Lin

et al. 2019

Human Mutation

View full text Add to dashboard Cite

show abstract

“…Somatic mosaicism is rarely reported in CMT, but offspring with CMT due to variants in MFN2, PMP22, GJB1 or MPZ and concurrent parental mosaic mutations, which cause milder phenotypes have been reported 89 . A sequencing trace [G] showing low levels of the mutant allele in the parent, which may be falsely recorded as negative, often gives a clue to possible mosaicism.…”

Section: False Positives and False Negativesmentioning

confidence: 99%

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

2019

View full text Add to dashboard Cite

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.

show abstract

“…Mitofusin 2 encoded by MFN2 is associated with the mobility of mitochondria in peripheral nerves (16–18). A mutation in this protein accounts for ~90% of severe and early onset CMT2 cases (7).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, the c.1190G>C; p.(R397P) missense mutation in MFN2 was successfully detected by WES, which indicates the power of WES to identify causative mutations for such genetically heterogeneous disorders. Mitofusin 2 encoded by MFN2 is associated with the mobility of mitochondria in peripheral nerves ( 16 – 18 ). A mutation in this protein accounts for ~90% of severe and early onset CMT2 cases ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing reveals a novel MFN2 missense mutation in a Chinese family with Charcot‑Marie‑Tooth type 2A

You

Wang

et al. 2018

Exp Ther Med

View full text Add to dashboard Cite

Charcot-Marie-Tooth (CMT) is a group of inherited peripheral neuropathies. To date, mutations in >80 genes are reportedly associated with CMT. Protein mitofusin 2 encoded by MFN2 serves an essential role in mitochondrial fusion and regulation of apoptosis, which has previously been reported to be highly associated with an axonal form of neuropathy (CMT2A). In the present study, a large Chinese family with severe CMT was reported and a genetic analysis of the disease was performed. A detailed physical examination for CMT was performed in 13 family members and electrophysiological examinations were performed in 3 affected family members. Whole-exome sequencing was performed on the proband, and the suspected variants were identified by Sanger sequencing. The pathogenicity of mutation was verified by restriction fragment length polymorphism analysis in the family followed by a bioinformatics analysis. A novel c.1190G>C; p.(R397P) mutation in the MFN2 gene was identified in the proband, and co-segregated between genotype and phenotype in the family. The substituted amino acid changed the hydrophobicity and charge characteristics of the mitofusin 2 coiled-coiled domain; thus it may affect its biological function. In summary, a novel pathogenic mutation was identified in a Chinese family with CMT, which expands the phenotypic and mutational spectrum of CMT2A, and provides evidence for prenatal interventions and more precise pharmacological treatments to this family.

show abstract

Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

Cited by 6 publications

References 21 publications

ATP1A1mutations cause intermediate Charcot‐Marie‐Tooth disease

ATP1A1mutations cause intermediate Charcot‐Marie‐Tooth disease

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

Exome sequencing reveals a novel MFN2 missense mutation in a Chinese family with Charcot‑Marie‑Tooth type 2A

Contact Info

Product

Resources

About