An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families

Ando, Masahiro; Higuchi, Yujiro; Okamoto, Yuji; Yuan, Jun‐Hui; Yoshimura, Akinobu; Takei, Jun; Taniguchi, Takaki; Hiramatsu, Yoshihiro; Sakiyama, Yusuke; Hashiguchi, Akihiro; Matsuura, Eiji; Nakagawa, Hiroto; Sonoda, Ken; Yamashita, Toru; Tamura, Akiko; Terasawa, Hideo; Mitsui, Jun; Ishiura, Hiroyuki; Tsuji, Shoji; Takashima, Hiroshi

doi:10.1038/s10038-022-01019-y

Cited by 6 publications

(8 citation statements)

References 19 publications

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“…This list seems long, but overall only 27/798 (9%) of patients with CMT in a large Japanese cohort were due to a mutation in NFL (Higuchi & Takashima, 2022). NH (P739S, L1003A, A1004G, P1007A, P1008A, L1010G, L1015G, L1020G, L1020I (Ando et al, 2022; Pipis et al, 2021; Yan et al, 2020)). Only eight out of 2494 (0.003%) of patients with CMT in a large UK cohort were due to a mutation in the NfH gene making this an extremely rare condition (Pipis et al, 2021).…”

Section: From Dna To Ptmmentioning

confidence: 99%

“…Only eight out of 2494 (0.003%) of patients with CMT in a large UK cohort were due to a mutation in the NfH gene making this an extremely rare condition (Pipis et al, 2021). All the NfH mutations in CMT affect the tail domain of the protein. SMA: NfH (P1007A in one single case (Ando et al, 2022)) PD: NfM (S336G (Lavedan et al, 2002)). It was suggested that this might represent a PD susceptibility factor similar to NFM (P725G and deletion of valine in position 829) (Han et al, 2005; Krüger et al, 2003).…”

Section: From Dna To Ptmmentioning

confidence: 99%

“…| 183 PETZOLD (P739S, L1003A, A1004G, P1007A, P1008A, L1010G, L1015G, L1020G, L1020I (Ando et al, 2022;Pipis et al, 2021;Yan et al, 2020)). Only eight out of 2494 (0.003%) of patients with CMT in a large UK cohort were due to a mutation in the NfH gene making this an extremely rare condition (Pipis et al, 2021).…”

Section: Nf Mutationsmentioning

confidence: 99%

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The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Petzold

2022

Journal of Neurochemistry

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Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), -internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot-Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post-translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease.Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33

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Section: From Dna To Ptmmentioning

confidence: 99%

Section: From Dna To Ptmmentioning

confidence: 99%

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The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Petzold

2022

Journal of Neurochemistry

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“…Our laboratory has published several papers on CMT/IPN since the 1990s 5–7,10,16,35,39–68 (Figure 5). Specifically, we have compiled the genetic profiles and onset characteristics of 1005 patients with CMT in Japan 67 .…”

Section: Introductionmentioning

confidence: 99%

Genetic research of inherited peripheral neuropathies

Higuchi

2023

Neurology & Clinical Neurosc

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BackgroundOur department has been conducting genetic research on hereditary neuropathies, with a focus on the Charcot–Marie–Tooth (CMT) disease and other inherited peripheral neuropathies for the past 20 years. The CMT disease is an untreatable disease characterized by progressive muscle weakness, atrophy, and sensory impairment, primarily affecting the peripheral nerves.Materials and MethodsIn our institution, we collected blood samples from patients with the CMT disease, nationwide, and performed comprehensive genetic testing to elucidate its underlying causes.ResultUsing next‐generation sequencing (NGS), we successfully discovered two novel causative genes of the CMT disease, membrane metalloendopeptidase (MME), and cytochrome c oxidase assembly factor 7, via whole exome analysis of previously unidentified cases. These findings, combined with the comprehensive analysis enabled by NGS, have significantly improved the diagnostic rate of this disease.ConclusionNotably, the MME gene has been reported as the most frequent causative gene for autosomal recessive CMT disease, attracting global attention and subsequent research efforts. Accurate genetic diagnosis for each patient serves as a crucial first step toward understanding hereditary diseases. The identification of new causes of the CMT disease can assist in elucidating the molecular mechanisms involved completely, further contributing to the development of effective treatment approaches, including gene therapies.

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“…Frameshift and missense mutations in NEFH have been convincingly linked to the pathogenesis of various neurological diseases, including Charcot-Marie-Tooth disease type 2CC [7][8][9][10] , spinal muscular atrophy 11 and Alzheimer's disease 12 .…”

Section: Introductionmentioning

confidence: 99%

Mutations in the tail domain of the neurofilament heavy chain gene increase the risk of amyotrophic lateral sclerosis

Marriott

Spargo

Khleifat

et al. 2022

Preprint

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Genetic variation in the neurofilament heavy chain gene (NEFH) has been convincingly linked to the pathogenesis of multiple neurodegenerative diseases, however, the relationship between NEFH mutations and ALS susceptibility has not been robustly explored. We therefore wanted to determine if genetic variants in NEFH modify ALS risk. We performed fixed and random effects model meta-analysis of published case-control studies reporting NEFH variant frequencies using next-generation sequencing, microarray or PCR-based approaches. Comprehensive screening and rare variant burden analysis of NEFH variation in the Project MinE ALS whole-genome sequencing data set was also conducted. We identified 12 case-control studies that reported NEFH variant frequencies, for a total of 9,496 samples (4,527 ALS cases and 4,969 controls). Fixed effects meta-analysis found that rare (MAF<1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.56, 95% CI 2.13-9.72, p<0.0001). A total of 591 rare NEFH variants, mostly novel (78.2%), were found in the Project MinE dataset (8,903 samples: 6,469 cases and 2,434 controls). Burden analysis showed ultra-rare (MAF <0.1%) pathogenic missense variants in the tail domain are associated with ALS (OR 1.94, 95% CI 0.86-4.37, Madsen-Browning p=0.039), replicating and confirming the meta-analysis finding. High-frequency rare (MAF 0.1-1%) tail in-frame deletions also confer susceptibility to ALS (OR 1.18, 95% CI 0.67-2.07, SKAT-O p=0.03), which supports previous findings. This study shows that NEFH tail domain variants are a risk factor of ALS and supports the inclusion of missense and in-frame deletion NEFH variants in ALS genetic screening panels.

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An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families

Cited by 6 publications

References 19 publications

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Genetic research of inherited peripheral neuropathies

Mutations in the tail domain of the neurofilament heavy chain gene increase the risk of amyotrophic lateral sclerosis

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