A novel stop codon mutation in the PMP22 gene associated with a variable phenotype

Abe, Kikue Terada; Lino, Angelina Maria Martins; Hirata, M. T. A.; Pavanello, Rita de Cássia M.; Brotto, Mario Wilson Iervolino; Marchiori, Paulo Eurípedes; Zatz, Mayana

doi:10.1016/j.nmd.2004.01.007

Cited by 9 publications

(5 citation statements)

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“…In these latter cases, it has been shown (in tissue cultures) that the mutated PMP22 protein is sequestrated in the endoplasmic reticulum [11]. A 3½ year-old girl with a PMP22 compound deletion has also been reported: a severe reduction or complete lack of PMP22 protein has been demonstrated in most of these cases [9,10,12]. In the sensory nerves of these patients, there is no myelin, so no tomacula and no other microscopical lesions (such as macrophages or apoptosis) were observed.…”

Section: Corresponding To Pmp22 -/-Micementioning

confidence: 98%

Rodent models with expression of PMP22: Relevance to dysmyelinating CMT and HNPP

Jouaud

Mathis

Richard

et al. 2019

Journal of the Neurological Sciences

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Background: Charcot-Marie-Tooth diseases (CMT) are due to abnormalities of many genes, the most frequent being linked to PMP22 (Peripheral Myelin Protein 22). In the past, only spontaneous genetic anomalies occurring in mouse mutants such as Trembler (Tr) mice were available; more recently, several rodent models have been generated for exploration of the pathophysiological mechanisms underlying these neuropathies.Methods: Based on the personal experience of our team, we describe here the pathological hallmarks of most of these animal models and compare them to the pathological features observed in some CMT patient nerves (CMT types 1A and E; hereditary neuropathy with liability to pressure palsies, HNPP).Results: we describe clinical data and detailed pathological analysis mainly by electron microscopy of the sciatic nerves of these animal models conducted in our laboratory; lesions of PMP22 deficient animals (KO and mutated PMP22) and PMP22 overexpressed models are described and compared to ultrastructural anomalies of nerve biopsies from CMT patients due to PMP22 gene anomalies. It is of note that while there are some similarities, there are also significant differences between the lesions in animal models and human cases. Such observations highlight the complex roles played by PMP22 in nerve development.Conclusion: It should be borne in mind that we require additional correlations between animal models of hereditary neuropathies and CMT patients to rationalize the development of efficient drugs.

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Section: Corresponding To Pmp22 -/-Micementioning

confidence: 98%

Rodent models with expression of PMP22: Relevance to dysmyelinating CMT and HNPP

Jouaud

Mathis

Richard

et al. 2019

Journal of the Neurological Sciences

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“…Inherited demyelination tends to produce uniform slowing of nerve conduction velocities without conduction block, and acquired demyelination nonuniform slowing and conduction block 128, 129, 154, 155. However, X‐linked CMT and HNPP commonly, and some CMT1A‐like patients with PMP22 point mutations rarely, have these later electrophysiological features of acquired demyelination,1, 97, 152, 153, 155 and may be mistakenly treated as chronic inflammatory demyelinating polyneuropathy (CIDP). Absence of a family history does not favor CIDP, as one‐third of patients with demyelinating CMT (CMT1 and Dejerine‐Sottas syndrome, DSS) have sporadic de novo mutations 23…”

Section: Neuropathiesmentioning

confidence: 99%

Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease

Greenberg

Walsh

2005

Muscle and Nerve

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Molecular genetic advances have led to refinements in the classification of inherited neuromuscular disease, and to methods of molecular testing useful for diagnosis and management of selected patients. Testing should be performed as targeted studies, sometimes sequentially, but not as wasteful panels of multiple genetic tests performed simultaneously. Accurate diagnosis through molecular testing is available for the vast majority of patients with inherited neuropathies, resulting from mutations in three genes (PMP22, MPZ, and GJB1); the most common types of muscular dystrophies (Duchenne and Becker, facioscapulohumeral, and myotonic dystrophies); the inherited motor neuron disorders (spinal muscular atrophy, Kennedy's disease, and SOD1 related amyotrophic lateral sclerosis); and many other neuromuscular disorders. The role of potential multiple genetic influences on the development of acquired neuromuscular diseases is an increasingly active area of research.

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“…[252627] In our study, patients with the G107D mutation in PMP22 showed typical CMT1 features. Interestingly, in previously reported literature, patients carrying the G107V mutation in PMP22 displayed a clinical phenotype ranging from symptomless to severely affected.…”

Section: Discussionmentioning

confidence: 61%

A Novel Missense Mutation in Peripheral Myelin Protein-22 Causes Charcot-Marie-Tooth Disease

Dong

Xiao

et al. 2017

Chinese Medical Journal

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Background:Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. A great number of causative genes have been described in CMT, and among them, the heterozygous duplication of peripheral myelin protein-22 (PMP22) is the major cause. Although the missense mutation in PMP22 is rarely reported, it has been demonstrated to be associated with CMT. This study described a novel missense mutation of PMP22 in a Chinese family with CMT phenotype.Methods:Targeted next-generation sequencing (NGS) was used to screen the causative genes in a family featured with an autosomal dominant demyelinating form of CMT. The potential variants identified by targeted NGS were verified by Sanger sequencing and classified according to the American College of Medical Genetics and Genomics standards and guidelines. Further cell transfection studies were performed to characterize the function of the novel variant.Results:Using targeted NGS, a novel heterozygous missense variant in PMP22 (c.320G>A, p.G107D) was identified. In vitro cell functional studies revealed that mutant PMP22 protein carrying p.G107D mutation lost the ability to reach the plasma membrane, was mainly retained in the endoplasmic reticulum, and induced cell apoptosis.Conclusions:This study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype, possibly through a toxic gain-of-function mechanism.

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A novel stop codon mutation in the PMP22 gene associated with a variable phenotype

Cited by 9 publications

References 54 publications

Rodent models with expression of PMP22: Relevance to dysmyelinating CMT and HNPP

Rodent models with expression of PMP22: Relevance to dysmyelinating CMT and HNPP

Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease

A Novel Missense Mutation in Peripheral Myelin Protein-22 Causes Charcot-Marie-Tooth Disease

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