title: NovelLMNAmutations cause an aggressive atypical neonatal progeria without progerin accumulation.
abstract: BACKGROUND
  Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations inLMNAleading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause.
  
  
  RESULTS
  Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia. However, pathological signs appear earlier, are more aggressive and present distinctive features including episodes of severe upper airway obstruction. Exome and Sanger sequencing allowed the identification of heterozygous de novo c.163G>A, p.E55K and c.164A>G, p.E55G mutations inLMNAas the alterations responsible for this disorder. Functional analyses demonstrated that fibroblasts from these patients suffer important dysfunctions in nuclear lamina, which generate profound nuclear envelope abnormalities but without progerin accumulation. These nuclear alterations found in patients' dermal fibroblasts were also induced by ectopic expression of the corresponding site-specificLMNAmutants in control human fibroblasts.
  
  
  CONCLUSIONS
  Our results demonstrate the causal role of p.E55K and p.E55G lamin A mutations in a disorder which manifests novel phenotypic features of the progeria spectrum characterised by neonatal presentation and aggressive clinical evolution, despite being caused by lamin A/C missense mutations with effective prelamin A processing.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Soria-Valles
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Dido
authors.initials: D
authors.lastname: Carrero
authors.affiliation: Servicio de Pediatría, Corporació Sanitària Parc Taulí, Sabadell, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gabau
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Velasco
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Quesada
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Clea
authors.initials: C
authors.lastname: Bárcena
authors.affiliation: Rehabilitation Center for Children and Adolescents, Pulderbos, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Moens
authors.affiliation: Division of Human Genetics, UCT Faculty of Health Sciences, Cape Town, South Africa.
authors.forename: Karen
authors.initials: K
authors.lastname: Fieggen
authors.affiliation: Department of Pediatrics Medi Clinic Hospital, Swakopmund, Namibia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Möhrcken
authors.affiliation: Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Owens
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Puente
authors.affiliation: Servicio de Pediatría, Corporació Sanitària Parc Taulí, Sabadell, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Asensio
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.affiliation: Servicio de Pediatría, Corporació Sanitària Parc Taulí, Sabadell, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Pérez
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Benoit
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.affiliation: Aix Marseille Université, INSERM, GMGF UMR_S 910 and Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: Department of Pediatrics, Academic Medical Center/Emma Pediatric Hospital, Amsterdam, The Netherlands.
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.affiliation: Aix Marseille Université, INSERM, GMGF UMR_S 910 and Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.
authors.forename: Annachiara
authors.initials: A
authors.lastname: De Sandre-Giovannoli
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
keywords: HGPS; aging