Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta
{"title":"POLR3B基因的一种新的从头变异与最大神经纤维的原发性轴突受累有关。","authors":"Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta","doi":"10.1111/jns.12602","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background and Aims</h3>\n \n <p><i>POLR3B</i> gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in <i>POLR3B</i> are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in <i>POLR3B</i> with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in <i>POLR3B</i>, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in <i>POLR3B</i>-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.</p>\n </section>\n </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2023-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12602","citationCount":"0","resultStr":"{\"title\":\"A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers\",\"authors\":\"Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta\",\"doi\":\"10.1111/jns.12602\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background and Aims</h3>\\n \\n <p><i>POLR3B</i> gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in <i>POLR3B</i> are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in <i>POLR3B</i> with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in <i>POLR3B</i>, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Interpretation</h3>\\n \\n <p>Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in <i>POLR3B</i>-related neuropathies. 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A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers
Background and Aims
POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.
Methods
Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.
Results
Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.
Interpretation
Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.
期刊介绍:
The Journal of the Peripheral Nervous System is the official journal of the Peripheral Nerve Society. Founded in 1996, it is the scientific journal of choice for clinicians, clinical scientists and basic neuroscientists interested in all aspects of biology and clinical research of peripheral nervous system disorders.
The Journal of the Peripheral Nervous System is a peer-reviewed journal that publishes high quality articles on cell and molecular biology, genomics, neuropathic pain, clinical research, trials, and unique case reports on inherited and acquired peripheral neuropathies.
Original articles are organized according to the topic in one of four specific areas: Mechanisms of Disease, Genetics, Clinical Research, and Clinical Trials.
The journal also publishes regular review papers on hot topics and Special Issues on basic, clinical, or assembled research in the field of peripheral nervous system disorders. Authors interested in contributing a review-type article or a Special Issue should contact the Editorial Office to discuss the scope of the proposed article with the Editor-in-Chief.