TY - JOUR
T1 - The heterozygous deletion c.1509_1510delAG in exon 14 of FUS causes an aggressive childhood-onset ALS with cognitive impairment
AU - Lanteri, Paola
AU - Meola, Irene
AU - Canosa, Antonio
AU - De Marco, Giovanni
AU - Lomartire, Annarosa
AU - Rinaudo, Maria Teresa
AU - Albamonte, Emilio
AU - Sansone, Valeria Ada
AU - Lunetta, Christian
AU - Manera, Umberto
AU - Vasta, Rosario
AU - Moglia, Cristina
AU - Calvo, Andrea
AU - Origone, Paola
AU - Chiò, Adriano
AU - Mandich, Paola
N1 - Funding Information:
This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02362405), the European Commission's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867), the Italian Ministry of Education, University and Research (Progetti di Ricerca di Rilevante Interesse Nazionale, PRIN, grant 2017SNW5MB), the Joint Programme - Neurodegenerative Disease Research (Strength and Brain-Mend projects), granted by Italian Ministry of Education, University and Research. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Italy. This his work was developed within the framework of the Department of Excellence grant of the Italian Ministry of Education, University and Research to the DINOGMI, University of Genoa, Italy.
Funding Information:
Paola Lanteri, Irene Meola, Antonio Canosa, Giovanni De Marco, Annarosa Lomartire, Maria Teresa Rinaudo, Emilio Albamonte Cristina Moglia, Maura Brunetti, Paola Origone, Paola Mandich report no conflicts of interest. Valeria Ada Sansone Sansone serves or has served as Scientific Consultant for Biogen, Avexis, Roche, PTC, Santhera, Dyne, Triplet, and Sarepta. Andrea Calvo has received research grant from Cytokinetics. Adriano Chiò serves on scientific advisory boards for Mitsubishi Tanabe USA, Roche, Avexis, Biogen, and Cytokinetics, and has received a research grant from Italfarmaco. Christian Lunetta received compensation for consulting services from Neuraltus, Cytokinetics, Mitsubishi Tanabe Pharma Europe, and Italfarmaco.
Publisher Copyright:
© 2021
PY - 2021/7
Y1 - 2021/7
N2 - We report a case of childhood-onset ALS with a FUS gene mutation presenting cognitive impairment and a rapid clinical progression. The patient, an 11-year-old girl, presented with right distal upper limb weakness and mild intellectual disability at the Griffith Mental Development Scales. The disease rapidly worsened and the patient became tetraplegic and bed-ridden 2 years after symptom onset. A c.1509_1510delAG mutation in exon 14 of the FUS gene was detected, resulting in a predicted truncated protein, p.G504Wfs*12, lacking the nuclear localization signal. The levels of FUS mRNA in the proband were not significantly different compared to controls. Western immunoblot analysis showed that one antibody (500–526) detected in the proband ~50% of the amount of FUS protein compared to controls, while 3 other antibodies (2–27, 400–450 and FUS C-terminal), which recognize both wild type and the mutated FUS, detected 60% to 75% of the amount of the protein. These findings indicate that p.G504Wfs*12 FUS is more prone to undergo post-translational modification respect to wild type FUS.
AB - We report a case of childhood-onset ALS with a FUS gene mutation presenting cognitive impairment and a rapid clinical progression. The patient, an 11-year-old girl, presented with right distal upper limb weakness and mild intellectual disability at the Griffith Mental Development Scales. The disease rapidly worsened and the patient became tetraplegic and bed-ridden 2 years after symptom onset. A c.1509_1510delAG mutation in exon 14 of the FUS gene was detected, resulting in a predicted truncated protein, p.G504Wfs*12, lacking the nuclear localization signal. The levels of FUS mRNA in the proband were not significantly different compared to controls. Western immunoblot analysis showed that one antibody (500–526) detected in the proband ~50% of the amount of FUS protein compared to controls, while 3 other antibodies (2–27, 400–450 and FUS C-terminal), which recognize both wild type and the mutated FUS, detected 60% to 75% of the amount of the protein. These findings indicate that p.G504Wfs*12 FUS is more prone to undergo post-translational modification respect to wild type FUS.
KW - FUS gene
KW - Juvenile amyotrophic lateral sclerosis
KW - Truncated FUS protein expression
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U2 - 10.1016/j.neurobiolaging.2021.01.029
DO - 10.1016/j.neurobiolaging.2021.01.029
M3 - Article
AN - SCOPUS:85101375527
SP - 130.e1-130.e7
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
ER -