Recessive hereditary motor and sensory neuropathy caused by
            <i>IGHMBP2</i>
            gene mutation

Shi, Chang He; Song, Bo; Luo, Hao; Mao, Cheng Yuan; Shang, Dan Dan; Cao, Yuan; Sun, Shi Lei; Wu, Jun; Zhuang, Zheng Ping; Xu, Yu

doi:10.1212/wnl.0000000000001747

Cited by 9 publications

(4 citation statements)

References 7 publications

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“…Mutations in genes involved in neuronal/muscular differentiation, and differentiation defects were linked to dHMNs. For example, IGHMBP2 leads to differentiation defects in motoneurons and is mutated in Charcot–Marie–Tooth (CMT) 2S; 73 MORC2 is a chromatin-remodeling protein regulating differentiation and mutated in CMT; 74 NDRG1 promotes differentiation and is mutated in CMT4D; 75 Sbf1/Sbf2 are epigenetic regulators of cell differentiation and are mutated in CMT 76 , 77 .…”

Section: Discussionmentioning

confidence: 99%

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

et al. 2021

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One of the critical events that regulates muscle cell differentiation is the replacement of the lamin B receptor (LBR)-tether with the lamin A/C (LMNA)-tether to remodel transcription and induce differentiation-specific genes. Here, we report that localization and activity of the LBR-tether are crucially dependent on the muscle-specific chaperone HSPB3 and that depletion of HSPB3 prevents muscle cell differentiation. We further show that HSPB3 binds to LBR in the nucleoplasm and maintains it in a dynamic state, thus promoting the transcription of myogenic genes, including the genes to remodel the extracellular matrix. Remarkably, HSPB3 overexpression alone is sufficient to induce the differentiation of two human muscle cell lines, LHCNM2 cells, and rhabdomyosarcoma cells. We also show that mutant R116P-HSPB3 from a myopathy patient with chromatin alterations and muscle fiber disorganization, forms nuclear aggregates that immobilize LBR. We find that R116P-HSPB3 is unable to induce myoblast differentiation and instead activates the unfolded protein response. We propose that HSPB3 is a specialized chaperone engaged in muscle cell differentiation and that dysfunctional HSPB3 causes neuromuscular disease by deregulating LBR.

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Section: Discussionmentioning

confidence: 99%

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

et al. 2021

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“…Unsurprisingly, the range of possible phenotypes associated with biallelic mutations in IGHMBP2 has increasingly expanded, including sensorimotor polyneuropathy (CMT2S) with onset ranging from <2 years 66 , 67 to late childhood, 68 , 69 with or without respiratory involvement. 70 Some cases can even present prenatally with talipes.…”

Section: Early Onset Neuronopathiesmentioning

confidence: 99%

Early onset hereditary neuronopathies: an update on non-5qmotor neuron diseases

Zambon

Pini

Bosco

et al. 2022

Brain

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Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement. Their cumulative estimated prevalence is 2.14/100.000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive, and X-linked inheritance. Despite the advances of next generation sequencing, more than 60% of patients with HMN remain genetically uncharacterised. Of note, we are increasingly aware of the broad range of phenotypes caused by pathogenic variants in the same gene and of the considerable clinical and genetic overlap between HMN and other conditions, such as Charcot-Marie-Tooth type 2 (CMT2; axonal), spinal muscular atrophy with lower extremities predominance (SMA-LED), neurogenic arthrogryposis multiplex congenita (AMC), and juvenile amyotrophic lateral sclerosis (ALS). Considering that most HMN present during childhood, in this review we primarily aim to summarise key clinical features of paediatric forms, including recent data on novel phenotypes, to help guide differential diagnosis and genetic testing. Secondly, we describe newly identified causative genes and molecular mechanisms, and discuss how the discovery of these is changing the paradigm through which we approach this group of conditions.

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“…We reviewed 10 papers reporting 26 AR‐CMT2S families from 2014 to 2023 worldwide 5,11–19 . With the eight AR‐CMT2S families we reported in 2017 and 2022 and the nine families reported here, there were 43 AR‐CMT2S families including 56 patients and 57 different mutations (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…We reviewed 10 papers reporting 26 AR-CMT2S families from 2014 to 2023 worldwide. 5,[11][12][13][14][15][16][17][18][19] With the eight AR-CMT2S families we reported in 2017 and 2022 and the nine families reported here, there were 43 AR-CMT2S families including 56 patients and 57 different T A B L E 1 Population analyses, bioinformatic predictions and American College of Medical Genetics and Genomics (ACMG) classifications of six IGHMBP2 novel mutations. F I G U R E 2 Legend on next page.…”

Section: Clinical and Genetic Features Of All Reported Ar-cmt2s Patie...mentioning

confidence: 99%

Genotype–phenotype correlations of AR‐CMT2S in a cohort of axonal Charcot–Marie–Tooth patients from Central South China

Liu,

Zeng,

et al. 2024

J Peripheral Nervous Sys

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Background and AimsThis study aimed to report nine Charcot–Marie–Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR‐CMT2S patients reported worldwide.MethodsGeneral information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR‐CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases.ResultsIn our CMT2 cohort, we detected 17 AR‐CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early‐onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR‐CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty‐nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile‐onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc.InterpretationAR‐CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR‐CMT2S. Furthermore, 17 AR‐CMT2S families could provide more resources for natural history study, drug research and development.

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Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation

Cited by 9 publications

References 7 publications

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

Early onset hereditary neuronopathies: an update on non-5qmotor neuron diseases

Genotype–phenotype correlations of AR‐CMT2S in a cohort of axonal Charcot–Marie–Tooth patients from Central South China

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