RT Journal Article SR Electronic T1 Novel LMNA mutations cause an aggressive atypical neonatal progeria without progerin accumulation JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 776 OP 785 DO 10.1136/jmedgenet-2015-103695 VO 53 IS 11 A1 Clara Soria-Valles A1 Dido Carrero A1 Elisabeth Gabau A1 Gloria Velasco A1 Víctor Quesada A1 Clea Bárcena A1 Marleen Moens A1 Karen Fieggen A1 Silvia Möhrcken A1 Martina Owens A1 Diana A Puente A1 Óscar Asensio A1 Bart Loeys A1 Ana Pérez A1 Valerie Benoit A1 Wim Wuyts A1 Nicolas Lévy A1 Raoul C Hennekam A1 Annachiara De Sandre-Giovannoli A1 Carlos López-Otín YR 2016 UL http://jmg.bmj.com/content/53/11/776.abstract AB 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 in LMNA leading 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.Methods and 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 in LMNA as 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-specific LMNA mutants 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.