PT - JOURNAL ARTICLE AU - Clara Soria-Valles AU - Dido Carrero AU - Elisabeth Gabau AU - Gloria Velasco AU - Víctor Quesada AU - Clea Bárcena AU - Marleen Moens AU - Karen Fieggen AU - Silvia Möhrcken AU - Martina Owens AU - Diana A Puente AU - Óscar Asensio AU - Bart Loeys AU - Ana Pérez AU - Valerie Benoit AU - Wim Wuyts AU - Nicolas Lévy AU - Raoul C Hennekam AU - Annachiara De Sandre-Giovannoli AU - Carlos López-Otín TI - Novel <em>LMNA</em> mutations cause an aggressive atypical neonatal progeria without progerin accumulation AID - 10.1136/jmedgenet-2015-103695 DP - 2016 Nov 01 TA - Journal of Medical Genetics PG - 776--785 VI - 53 IP - 11 4099 - http://jmg.bmj.com/content/53/11/776.short 4100 - http://jmg.bmj.com/content/53/11/776.full SO - J Med Genet2016 Nov 01; 53 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&gt;A, p.E55K and c.164A&gt;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.