Congenital insensitivity to pain: a novel mutation affecting a U12-type intron causes multiple aberrant splicing of SCN9A
| Autor: | Raffaella Lombardi, Giuseppe Lauria, Evren Gumus, Margherita Marchi, Mirna Andelic, Ilaria D'Amato, Daniele Cartelli, Erika Salvi |
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| Přispěvatelé: | Klinische Neurowetenschappen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience |
| Rok vydání: | 2021 |
| Předmět: |
Proband
Pain Insensitivity Congenital Pain NA(V)1.7 Biology medicine.disease_cause Exon RARE medicine Humans Genetics Mutation SCN9A NAV1.7 Voltage-Gated Sodium Channel Intron RNA medicine.disease Introns SODIUM Alternative Splicing Anesthesiology and Pain Medicine Neurology Congenital insensitivity to pain RNA splicing Loss of function mutation Neurology (clinical) SCN9A Gene U12-type introns |
| Zdroj: | Pain, 163(7), E882-E887. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 1872-6623 0304-3959 |
| Popis: | Mutations in the alpha subunit of voltage-gated sodium channel 1.7 (NaV1.7), encoded by SCN9A gene, play an important role in the regulation of nociception and can lead to a wide range of clinical outcomes, ranging from extreme pain syndromes to congenital inability to experience pain. To expand the phenotypic and genotypic spectrum of SCN9A-related channelopathies, we describe the proband, a daughter born from consanguineous parents, who had pain insensitivity, diminished temperature sensation, foot burns, and severe loss of nociceptive nerve fibers in the epidermis. Next-generation sequencing of SCN9A (NM_002977.3) revealed a novel homozygous substitution (c.377+7TG) in the donor splice site of intron 3. As the RNA functional testing is challenging, the in silico analysis is the first approach to predict possible alterations. In this case, the computational analysis was unable to identify the splicing consensus and could not provide any prediction for splicing defects. The affected intron indeed belongs to the U12 type, a family of introns characterised by noncanonical consensus at the splice sites, accounting only for 0.35% of all human introns, and is not included in most of the training sets for splicing prediction. A functional study on proband RNA showed different aberrant transcripts, where exon 3 was missing and an intron fragment was included. A quantification study using real-time polymerase chain reaction showed a significant reduction of the NaV1.7 canonical transcript. Collectively, these data widen the spectrum of SCN9A-related insensitivity to pain by describing a mutation causing NaV1.7 deficiency, underlying the nociceptor dysfunction, and highlight the importance of molecular investigation of U12 introns' mutations despite the silent prediction. |
| Databáze: | OpenAIRE |
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