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101. Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report

Author

Frédérique Magdinier, Marc Bartoli, Stéphane Roche, Karine Nguyen, Rafaëlle Bernard, Julie Dumonceaux, Camille Dion, Virginie Mariot, Emmanuelle Salort Campana, Marie-Cécile Gaillard, Nicolas Lévy, Charlene Chaix, Armand Tasmadjian, Shahram Attarian, Francesca Puppo, Catherine Vovan, Killian Mazaleyrat, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Facio-Scapulo-Humeral Dystrophy, Chromosomal Proteins, Non-Histone, DUX4, Case Report, Haploinsufficiency, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, 03 medical and health sciences, Exon, DNA combing, Chromosome Segregation, medicine, Genetics, Humans, Genetics(clinical), Muscular dystrophy, Genetics (clinical), Exome sequencing, Mutation, FSHD, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, DNA methylation, SMCHD1, Haplotype, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Molecular biology, Muscular Dystrophy, Facioscapulohumeral, Pedigree, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Epigenetics, Chromosomes, Human, Pair 4, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Microsatellite Repeats
Abstract

Background The main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence of D4Z4 reduction (FSHD2). In 70-80 % of these patients, variants of the SMCHD1 gene segregate with 4qA haplotypes and D4Z4 hypomethylation. Case presentation We report a family presenting with neuromuscular symptoms reminiscent of FSHD but without D4Z4 copy reduction. We characterized the 4q35 region using molecular combing, searched for mutation in the SMCHD1 gene and determined D4Z4 methylation level by sodium bisulfite sequencing. We further investigated the impact of the SMCHD1 mutation at the protein level and on the NMD-dependent degradation of transcript. In muscle, we observe moderate but significant reduction in D4Z4 methylation, not correlated with DUX4-fl expression. Exome sequencing revealed a heterozygous insertion of 7 bp in exon 37 of the SMCHD1 gene producing a loss of frame with premature stop codon 4 amino acids after the insertion (c.4614-4615insTATAATA). Both wild-type and mutated transcripts are detected. Conclusion The truncated protein is absent and the full-length protein level is similar in patients and controls indicating that in this family, FSHD is not associated with SMCHD1 haploinsufficiency. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0328-9) contains supplementary material, which is available to authorized users.

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102. The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4

Author

Livia Parodi, Mathieu Barbier, Maxime Jacoupy, Claire Pujol, François-Xavier Lejeune, Pauline Lallemant-Dudek, Typhaine Esteves, Maartje Pennings, Erik-Jan Kamsteeg, Marine Guillaud-Bataille, Guillaume Banneau, Giulia Coarelli, Badreddine Mohand Oumoussa, Matthew J. Fraidakis, Giovanni Stevanin, Christel Depienne, Bart van de Warrenburg, Alexis Brice, Alexandra Durr, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Bordeaux (UB), Radboud University Medical Center [Nijmegen], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 'Attikon' University Hospital, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], and We are deeply grateful to the patients for their participation. We thank the DNA and Cells Bank of the Paris Brain Institute (Institut du Cerveau, ICM) (Sylvie Forlani and Ludmila Jornea) and all the SPATAX network collaborators for their dedicated support: Mathieu Anheim, Dominique Bonneau, Rabab Debs, Claire Ewenczyk, Cyril Goizet, Solveig Heide, Isabelle Le Ber, Timothée Lenglet, Cecilia Marelli, Karine Nguyen, Diana Rodriguez, Tanya Stojkovic, Alina Maria Tataru, and Christine Tranchant.

Subjects
Serine-tRNA Ligase, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Spastin, SARS2, Spastic Paraplegia, Hereditary, Hereditary spastic paraplegia, Medizin, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Genetic modifier, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Mitochondria, Mutation, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics (clinical), Genome-Wide Association Study
Abstract

Item does not contain fulltext PURPOSE: Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset. METHODS: We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553). RESULTS: We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel-Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients. CONCLUSION: SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy.

Published
2022

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