title: Truncated prelamin A expression in HGPS-like patients: a transcriptional study.
abstract: Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.
authors: Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France.
authors: Florian
authors: F
authors: Barthélémy
authors: Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France.
authors: Claire
authors: 0000000194902643
authors: C
authors: Navarro
authors: Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France.
authors: Racha
authors: R
authors: Fayek
authors: Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France.
authors: Nathalie
authors: N
authors: Da Silva
authors: 1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors: Patrice
authors: P
authors: Roll
authors: 1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors: Sabine
authors: S
authors: Sigaudy
authors: Department of Pathology, University of Washington, Seattle, WA, USA.
authors: Junko
authors: J
authors: Oshima
authors: 1] Inserm, U974, Paris, France [2] Université Pierre et Marie Curie- Paris 6, UM 76, CNRS, UMR 7215, Institut de Myologie, Paris, France [3] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France.
authors: Gisèle
authors: G
authors: Bonne
authors: 4th Department of Pediatrics of the Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece.
authors: Kyriaki
authors: K
authors: Papadopoulou-Legbelou
authors: 4th Department of Pediatrics of the Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece.
authors: Athanasios E
authors: AE
authors: Evangeliou
authors: 1st Department of Neurology of the Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.
authors: Martha
authors: M
authors: Spilioti
authors: Département de génétique, IFR 94-Institut de Recherche Necker Enfants Malades- CHU Paris-Hôpital Necker-Enfants Malades, Paris, France.
authors: Martine
authors: M
authors: Lemerrer
authors: Department of Laboratory Medicine, IGMD, Nijmegen, The Netherlands.
authors: Ron A
authors: RA
authors: Wevers
authors: Clinical Biochemical Genetics, Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, USA.
authors: Eva
authors: E
authors: Morava
authors: 1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors: Andrée
authors: A
authors: Robaglia-Schlupp
authors: 1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors: Nicolas
authors: N
authors: Lévy
authors: 1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors: Marc
authors: M
authors: Bartoli
authors: 1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors: Annachiara
authors: A
authors: De Sandre-Giovannoli
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000473:pathology; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011371:Progeria / Q000235:genetics* / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing; D014158:Transcription, Genetic
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D011498:Protein Precursors; D022821:RNA Splice Sites
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