Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea

Lim, Si On; Jung, Na Young; Lee, Ah Jin; Choi, Hee Ji; Kwon, Hye Mi; Son, Wonseok; Nam, Soo Hyun; Choi, Byung Ok; Chung, Ki Wha

doi:10.3390/genes13030462

Cited by 5 publications

(5 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although PMP22 de novo mutations have been frequently reported by other studies [ 9 , 15 ], the rate was higher than those shown in the other CMT gene mutations in Korea compared to the 45.0% and 18.7% of the trio families with the MPZ mutations and PMP22 duplication causing CMT1A [ 47 ], respectively. Only two and one de novo cases were observed in 11 families with small heat shock protein (sHSP) gene mutations [ 48 ] and 13 families with aminoacyl tRNA-synthetase (ARS) gene mutations [ 49 ]. In particular, c.215C>T (p.S72L) de novo mutation, which was observed in 4 of 5 families with the corresponding mutation, is suggested to locate in a mutational hotspot.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

Jung

Kwon

Nam

et al. 2022

Genes

Self Cite

View full text Add to dashboard Cite

Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype–phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.

show abstract

Section: Discussionmentioning

confidence: 99%

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

Jung

Kwon

Nam

et al. 2022

Genes

Self Cite

View full text Add to dashboard Cite

show abstract

“…Missense mutations of the K141 residue of HSPB8 have been associated with dHMN and CMT2L disease, which mainly targets motor neurons [ 11 , 12 , 14 ]. We found three mutations of the K141 residue (K141N, K141E, and K141T) in HSPB8 from a patient cohort with inherited peripheral neuropathy [ 21 ]. The vulnerability of motor neurons to mutated HSPB8 has been reported by overexpression studies in primary neuronal motor neuron cultures in which K141E and K141N HSPB8 caused neurite degeneration [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in Drosophila Models

et al. 2023

Self Cite

View full text Add to dashboard Cite

Charcot–Marie–Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated with hereditary neuropathies, including CMT. HSPB8 is a member of the small heat shock protein family sharing a highly conserved α-crystallin domain that is critical to its chaperone activity. In this study, we modeled HSPB8 mutant-induced neuropathies in Drosophila. The overexpression of human HSPB8 mutants in Drosophila neurons produced no significant defect in fly development but led to a partial reduction in fly lifespan. Although these HSPB8 mutant genes failed to induce sensory abnormalities, they reduced the motor activity of flies and the mitochondrial functions in fly neuronal tissue. The motor defects and mitochondrial dysfunction were successfully restored by PINK1 and parkin, which are Parkinson’s disease-associated genes that have critical roles in maintaining mitochondrial function and integrity. Consistently, kinetin riboside, a small molecule amplifying PINK1 activity, also rescued the loss of motor activity in our HSPB8 mutant model.

show abstract

“…One of the most common causes of dHMN are dominant mutations in HSPB1 , the prevalence of which vary between 5 and 10% in different series [3 ▪ –5 ▪ ,6,10]. Recessive inheritance has been reported in few cases [11,12]. Patients carrying the same HSPB1 mutation can be diagnosed with either dHMN or CMT2 [3 ▪ ].…”

Section: Classic Distal Hereditary Motor Neuropathiesmentioning

confidence: 99%

Hereditary motor neuropathies

Frasquet

Sevilla

2022

Current Opinion in Neurology

View full text Add to dashboard Cite

Purpose of reviewDistal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons. In this review, we will provide an overview of dHMN, and we will correlate the distinct clinical subtypes with their causative genes, focusing on the most recent advances in the field. Recent findingsDespite the massive use of new-generation sequencing (NGS) and the discovery of new genes, only a third of dHMN patients receive a molecular diagnosis. Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1. Mutations in SORD are the most frequent cause of autosomal recessive forms of dHMN. As a result of these findings, the potential benefits of some pharmacological compounds are being studied in cell and animal models, mainly targeting axonal transport and metabolic pathways. SummaryDespite the wide use of NGS, the diagnosis of dHMN remains a challenge. The low prevalence of dHMN makes international cooperation necessary in order to discover new genes and causal mechanisms. Genetic diagnosis of patients and identification of new pathomechanism are essential for the development of therapeutical clinical trials.

show abstract

Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea

Cited by 5 publications

References 36 publications

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in Drosophila Models

Hereditary motor neuropathies

Contact Info

Product

Resources

About