A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms

Antonio Canosa, Giovanni De Marco, Annarosa Lomartire, Maria Teresa Rinaudo, Ferdinando Di Cunto, Emilia Turco, Marco Barberis, Maura Brunetti, Federico Casale, Cristina Moglia, Andrea Calvo, Stefan L Marklund, Peter M Andersen, Gabriele Mora, Adriano Chiò

Research output: Contribution to journalArticle

Abstract

We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.

Original languageEnglish
Pages (from-to)189.e11-189.e17
JournalNeurobiology of Aging
Volume72
DOIs
Publication statusPublished - Dec 2018

Fingerprint

Nonsense Codon
Mutation
Alleles
Nerve Tissue
Messenger RNA
Frameshift Mutation
Proteins
Poisons
Motor Neurons
Proteasome Endopeptidase Complex
Polyacrylamide Gel Electrophoresis
Erythrocytes
Western Blotting
Polymerase Chain Reaction
Wounds and Injuries

Cite this

A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient : insights into the underlying pathomechanisms. / Canosa, Antonio; De Marco, Giovanni; Lomartire, Annarosa; Rinaudo, Maria Teresa; Di Cunto, Ferdinando; Turco, Emilia; Barberis, Marco; Brunetti, Maura; Casale, Federico; Moglia, Cristina; Calvo, Andrea; Marklund, Stefan L; Andersen, Peter M; Mora, Gabriele; Chiò, Adriano.

In: Neurobiology of Aging, Vol. 72, 12.2018, p. 189.e11-189.e17.

Research output: Contribution to journalArticle

Canosa, A, De Marco, G, Lomartire, A, Rinaudo, MT, Di Cunto, F, Turco, E, Barberis, M, Brunetti, M, Casale, F, Moglia, C, Calvo, A, Marklund, SL, Andersen, PM, Mora, G & Chiò, A 2018, 'A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms', Neurobiology of Aging, vol. 72, pp. 189.e11-189.e17. https://doi.org/10.1016/j.neurobiolaging.2018.08.014
Canosa, Antonio ; De Marco, Giovanni ; Lomartire, Annarosa ; Rinaudo, Maria Teresa ; Di Cunto, Ferdinando ; Turco, Emilia ; Barberis, Marco ; Brunetti, Maura ; Casale, Federico ; Moglia, Cristina ; Calvo, Andrea ; Marklund, Stefan L ; Andersen, Peter M ; Mora, Gabriele ; Chiò, Adriano. / A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient : insights into the underlying pathomechanisms. In: Neurobiology of Aging. 2018 ; Vol. 72. pp. 189.e11-189.e17.
@article{8df48a99160847e7a1970cf1d5a195f7,
title = "A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms",
abstract = "We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.",
author = "Antonio Canosa and {De Marco}, Giovanni and Annarosa Lomartire and Rinaudo, {Maria Teresa} and {Di Cunto}, Ferdinando and Emilia Turco and Marco Barberis and Maura Brunetti and Federico Casale and Cristina Moglia and Andrea Calvo and Marklund, {Stefan L} and Andersen, {Peter M} and Gabriele Mora and Adriano Chi{\`o}",
note = "Copyright {\circledC} 2018 Elsevier Inc. All rights reserved.",
year = "2018",
month = "12",
doi = "10.1016/j.neurobiolaging.2018.08.014",
language = "English",
volume = "72",
pages = "189.e11--189.e17",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient

T2 - insights into the underlying pathomechanisms

AU - Canosa, Antonio

AU - De Marco, Giovanni

AU - Lomartire, Annarosa

AU - Rinaudo, Maria Teresa

AU - Di Cunto, Ferdinando

AU - Turco, Emilia

AU - Barberis, Marco

AU - Brunetti, Maura

AU - Casale, Federico

AU - Moglia, Cristina

AU - Calvo, Andrea

AU - Marklund, Stefan L

AU - Andersen, Peter M

AU - Mora, Gabriele

AU - Chiò, Adriano

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/12

Y1 - 2018/12

N2 - We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.

AB - We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.

U2 - 10.1016/j.neurobiolaging.2018.08.014

DO - 10.1016/j.neurobiolaging.2018.08.014

M3 - Article

C2 - 30236613

VL - 72

SP - 189.e11-189.e17

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -