Axonal Charcot-Marie-Tooth neuropathy concurrent with distal and proximal weakness by translational elongation of the 3′ UTR in NEFH

Da Eun Nam, Sung Chul Jung, Da Hye Yoo, Sun Seong Choi, Sung Yum Seo, Gwang Hoon Kim, Song Ja Kim, Soo Hyun Nam, Byung Ok Choi, Ki Wha Chung

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Mutations in the NEFH gene encoding the heavy neurofilament protein are usually associated with neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS). Recently, frameshift variants in NEFH (p.Asp1004Glnfs*58 and p.Pro1008Alafs*56) have been reported to be the underlying cause of axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC). The frameshift mutation resulted in a stop loss and translation of a cryptic amyloidogenic element (CAE) encoded by the 3′ untranslated region (UTR). This study also identified a de novo c.3015_3027dup frameshift mutation predicting p.Lys1010Glnfs*57 in NEFH from a CMT2 family with an atypical clinical symptom of prominent proximal weakness. This mutation is located near the previously reported frameshift mutations, suggesting a mutational hotspot. Lower limb magnetic resonance imaging (MRI) revealed marked hyperintense signal changes in the thigh muscles compared with those in the calf muscles. Therefore, this study suggests that the stop loss and translational elongations by the 3′ UTR of the NEFH mutations may be a relatively frequent genetic cause of axonal peripheral neuropathy with the specific characteristics of proximal dominant weakness.

Original languageEnglish
Pages (from-to)200-207
Number of pages8
JournalJournal of the Peripheral Nervous System
Volume22
Issue number3
DOIs
StatePublished - Sep 2017

Bibliographical note

Funding Information:
This study was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare (HI12C0135, HI14C3484 and HI15C1560) and the National Research Foundation funded by MSIP (2017R1A2A2A05001356 and 2017R1A2B2004699), Republic of Korea.

Publisher Copyright:
© 2017 Peripheral Nerve Society

Keywords

  • CMT2CC
  • NEFH
  • cryptic amyloidogenic element (CAE)
  • frameshift mutation

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