Severe Neuropathy After Diphtheria-Tetanus-Pertussis Vaccination in a Child Carrying a Novel Frame-Shift Mutation in the Small Heat-Shock Protein 27 Gene

Mandich, Paola; Grandis, Marina; Varese, Alessandra; Geroldi, Alessandro; Acquaviva, Massimo; Ciotti, Paola; Gulli, Rossella; Doria-Lamba, Laura; Fabrizi, Gian Maria; Giribaldi, Gaia; Pizzuti, Antonio; Schenone, Angelo; Bellone, Emilia

doi:10.1177/0883073809334387

Cited by 31 publications

(24 citation statements)

References 4 publications

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“…One frame shift mutation (p.P159fsX200, c.476–477delCT) in HspB1 has been reported (Table 1) [38, 60]. This mutation results in an aberrant sequence spanning the 3'-end of the α-crystallin domain and the C-terminal extension (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Benndorf

Martin

Pond

et al. 2014

Mutation Research/Reviews in Mutation Research

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Mutations in four of the ten human small heat shock proteins (sHSP) are associated with various forms of motor neuropathies and myopathies. In HspB1, HspB3, and HspB8 all known mutations cause motor neuropathies, whereas in HspB5 they cause myopathies. Several features are common to the majority of these mutations: (i) they are missense mutations, (ii) most associated disease phenotypes exhibit a dominant inheritance pattern and late disease onset, (iii) in the primary protein sequences, the sites of most mutations are located in the conserved α-crystallin domain and the variable C-terminal extensions, and (iv) most human mutation sites are highly conserved among the vertebrate orthologs and have been historically exposed to significant purifying selection. In contrast, a minor fraction of these mutations deviate from these rules: they are (i) frame shifting, nonsense, or elongation mutations, (ii) associated with recessive or early onset disease phenotypes, (iii) positioned in the N-terminal domain of the proteins, and (iv) less conserved among the vertebrates and were historically not subject to a strong selective pressure. In several vertebrate sHSPs (including primate sHSPs), homologous sites differ from the human sequence and occasionally even encode the same amino acid residues that cause the disease in humans. Apparently, a number of these mutations sites are not crucial for the protein function in single species or entire taxa, and single species even seem to have adopted mechanisms that compensate for potentially adverse effects of 'mutant-like' sHSPs. The disease-associated dominant sHSP missense mutations have a number of cellular consequences that are consistent with gain-of-function mechanisms of genetic dominance: dominant-negative effects, the formation of cytotoxic amyloid protein oligomers and precipitates, disruption of cytoskeletal networks, and increased downstream enzymatic activities. Future therapeutic concepts should aim for reducing these adverse effects of mutant sHSPs in patients. Indeed, initial experimental results are encouraging.

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Section: Resultsmentioning

confidence: 99%

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Benndorf

Martin

Pond

et al. 2014

Mutation Research/Reviews in Mutation Research

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“…HSPB1 mutations have been reported in families from Belgium, France, Russia, England, Croatia, Austria, Korea, China, India, Japan and Pakistan [3,4,[11][12][13][14][15][16]. Only two descriptions of mutations in this gene from the Italian population are available [19,20].…”

Section: Discussionmentioning

confidence: 99%

A novel HSPB1 mutation in an Italian patient with CMT2/dHMN phenotype

Luigetti

Fabrizi

Madia

et al. 2010

Journal of the Neurological Sciences

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“…An autosomal recessive mutation in HSPB1 has been reported with a similar age of onset and clinical phenotype 17. The average age of onset is 30 years but can be as late as 6319 and as young as 4 years of age 22. The phenotype is characterised by progressive distal weakness in the legs with mild or subclinical sensory involvement.…”

Section: Dhmn Causative Genesmentioning

confidence: 98%

The distal hereditary motor neuropathies

Rossor

Kalmár²,

Greensmith³

et al. 2011

J Neurol Neurosurg Psychiatry

196

183

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The distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot-Marie-Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.

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Severe Neuropathy After Diphtheria-Tetanus-Pertussis Vaccination in a Child Carrying a Novel Frame-Shift Mutation in the Small Heat-Shock Protein 27 Gene

Cited by 31 publications

References 4 publications

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites

A novel HSPB1 mutation in an Italian patient with CMT2/dHMN phenotype

The distal hereditary motor neuropathies

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