A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers

Author:

Geroldi Alessandro1ORCID,Tozza Stefano2ORCID,Fiorillo Chiara13,Nolano Maria2,Fossa Paola4,Vitale Floriana2,Domi Regi4,Gaudio Andrea5,Mammi Alessia1,Patrone Serena1,Barbera Andrea La5,Origone Paola15,Ponti Clarissa15,Sanguineri Francesca15,Zara Federico16,Cataldi Matteo13,Salpietro Vincenzo16,Venturi Consuelo Barbara7,Massucco Sara18,Schenone Angelo18,Manganelli Fiore2,Mandich Paola15,Bellone Emilia15,Gotta Fabio5

Affiliation:

1. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences University of Genoa Genoa Italy

2. Department of Neuroscience, Reproductive and Odontostomatological Sciences University of Naples Federico II Naples Italy

3. Child Neuropsychiatric Unit IRCCS Institute G. Gaslini Genoa Italy

4. Department of Pharmacy University of Genoa Genoa Italy

5. OU Medical Genetics IRCCS Ospedale Policlinico San Martino Genoa Italy

6. Medical Genetic Unit IRCCS Institute G. Gaslini Genoa Italy

7. OU Pathological Anatomy IRCCS Ospedale Policlinico San Martino Genoa Italy

8. OU Neurology Clinic IRCCS Ospedale Policlinico San Martino Genoa Italy

Abstract

AbstractBackground and AimsPOLR3B 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.MethodsNerve 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.ResultsSince 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.InterpretationNeurophysiological 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.

Publisher

Wiley

Subject

Neurology (clinical),General Neuroscience

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. POLR3B de novo variants are a rare cause of infantile myoclonic epilepsy;Seizure: European Journal of Epilepsy;2024-10

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