Phenotype and natural history of inherited neuropathies caused by<i>HSJ1</i>c.352+1G&gt;A mutation

Frasquet, Marina; Chumillas, María José; Vílchez, Juan J.; Márquez-Infante, Celedonio; Palau, Francesc; Vázquez-Costa, Juan Francisco; Lupo, Vincenzo; Espinós, Carmen; Sevilla, Teresa

doi:10.1136/jnnp-2015-312890

Cited by 16 publications

(24 citation statements)

References 5 publications

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“…Recessive DNAJB2 mutations (Table 4) have been identified as a so far uncommon cause of peripheral neuropathies, which may present as distal hereditary motor neuropathy (dHMN) or sensory and motor neuropathy (Charcot-Marie-Tooth disease type 2, CMT2) [112,113,[127][128][129]. 2 dHMN, parkinsonism [129] DNAJB2 was first associated to disease by Blumen and colleagues [112], who identified a homozygous c.352+1G>A splice donor site mutation in a family with dHMN.…”

Section: Dnajb2 Mutations In Neuromuscular Diseasementioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

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Section: Dnajb2 Mutations In Neuromuscular Diseasementioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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“…The expression of MME in the sural nerve was significantly decreased in patients with autosomal‐recessive CMT2, while its expression was only mildly decreased in our patient, implying a subclinically biochemical alteration in sensory nerve, even though the patient currently presented with a dHMN phenotype. Therefore, a long‐term follow‐up is warranted in order to determine whether sensory disturbances would involve in the lower limbs of patients with autosomal‐recessive MME variants as the disease progresses …”

Section: Discussionmentioning

confidence: 99%

Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

Hong

Yao

et al. 2019

Ann Clin Transl Neurol

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Objective To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. Methods Whole‐exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. Results The clinical features of the patients showed late‐onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co‐segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense‐mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. Interpretation Variants in the MME gene were associated with not only a Charcot‐Marie‐Tooth neuropathy phenotype but also with an autosomal‐recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.

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“…To date, the remaining known patients with mutations in the DNAJB2 gene carry the c.352+1G>A mutation in homozygosis: 5 families from Spain (Frasquet et al, 2016; Lupo et al, 2016) and one from Brazil (Teive et al, 2015). These Spanish families were investigated by haplotype analysis and they carried the same homozygous haplotype.…”

Section: The Growing List Of Chaperones Involved In Distal Hereditarymentioning

confidence: 99%

“…Hence, the DNAJB2 c.352+1G>A mutation appears to be a founder event (Lupo et al, 2016), and it is shared with a family reported elsewhere (Blumen et al, 2012). The patients in Spain displayed a dHMN or CMT2 phenotype and, in some cases, initial clinical manifestations that were consistent with dHMN and that subsequently evolved to CMT2 (Frasquet et al, 2016). Moreover, the peripheral motor neuropathy recently described in a Brazilian family carrying the DNAJB2 c.352+1G>A mutation was associated with parkinsonism and cerebellar ataxia (Teive et al, 2015).…”

Section: The Growing List Of Chaperones Involved In Distal Hereditarymentioning

confidence: 99%

“…Moreover, the peripheral motor neuropathy recently described in a Brazilian family carrying the DNAJB2 c.352+1G>A mutation was associated with parkinsonism and cerebellar ataxia (Teive et al, 2015). Some patients show parkinsonian symptoms (Frasquet et al, 2016; Sanchez et al, 2016; Teive et al, 2015), which probably are due to the DNAJB2 mutations. Other additional symptoms such as cerebellar ataxia may be coincidental.…”

Section: The Growing List Of Chaperones Involved In Distal Hereditarymentioning

confidence: 99%

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Chaperonopathies: Spotlight on Hereditary Motor Neuropathies

Lupo

Aguado

Knecht

et al. 2016

Front. Mol. Biosci.

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Distal hereditary motor neuropathies (dHMN) are a group of rare hereditary neuromuscular disorders characterized by an atrophy that affects peroneal muscles in the absence of sensory symptoms. To date, 23 genes are thought to be responsible for dHMN, four of which encode chaperones: DNAJB2, which encodes a member of the HSP40/DNAJ co-chaperone family; and HSPB1, HSPB3, and HSPB8, encoding three members of the small heat shock protein family. While around 30 different mutations in HSPB1 have been identified, the remaining three genes are altered in many fewer cases. Indeed, a mutation of HSPB3 has only been described in one case, whereas a few cases have been reported carrying mutations in DNAJB2 and HSPB8, most of them caused by a founder c.352+1G>A mutation in DNAJB2 and by mutations affecting the K141 residue in the HSPB8 chaperone. Hence, their rare occurrence makes it difficult to understand the pathological mechanisms driven by such mutations in this neuropathy. Chaperones can assemble into multi-chaperone complexes that form an integrated chaperone network within the cell. Such complexes fulfill relevant roles in a variety of processes, such as the correct folding of newly synthesized proteins, in which chaperones escort them to precise cellular locations, and as a response to protein misfolding, which includes the degradation of proteins that fail to refold properly. Despite this range of functions, mutations in some of these chaperones lead to diseases with a similar clinical profile, suggesting common pathways. This review provides an overview of the genetics of those dHMNs that share a common disease mechanism and that are caused by mutations in four genes encoding chaperones: DNAJB2, HSPB1, HSPB3, and HSPB8.

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Phenotype and natural history of inherited neuropathies caused byHSJ1c.352+1G>A mutation

Cited by 16 publications

References 5 publications

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

Chaperonopathies: Spotlight on Hereditary Motor Neuropathies

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