NovelLMNAmutations cause an aggressive atypical neonatal progeria without progerin accumulation
Authors: Gloria Velasco
Clea B√°rcena
Valerie Benoit
Wim Wuyts
V√≠ctor Quesada
Carlos L√≥pez-Ot√≠n
Clara Soria-Valles
Martina Owens
Nicolas L√©vy
Karen Fieggen
Dido Carrero
Marleen Moens
Diana A Puente
√ìscar Asensio
Silvia M√∂hrcken
Elisabeth Gabau
Ana P√©rez
Bart Loeys
Raoul C Hennekam
Annachiara De Sandre-Giovannoli
Journal: Journal of Medical Genetics (2016)
Discipline: CLINICAL MEDICINE
Keywords: HGPS; aging.
Affiliations: Departamento de Bioqu√≠mica y Biolog√≠a Molecular, Facultad de Medicina, Instituto Universitario de Oncolog√≠a (IUOPA), Universidad de Oviedo, Oviedo, Spain., Servicio de Pediatr√≠a, Corporaci√≥ Sanit√†ria Parc Taul√≠, Sabadell, Spain., Rehabilitation Center for Children and Adolescents, Pulderbos, Belgium., Division of Human Genetics, UCT Faculty of Health Sciences, Cape Town, South Africa., Department of Pediatrics Medi Clinic Hospital, Swakopmund, Namibia., Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK., Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium., Aix Marseille Universit√©, INSERM, GMGF UMR_S 910 and D√©partement de G√©n√©tique M√©dicale et de Biologie Cellulaire, AP-HM, H√¥pital d'Enfants de la Timone, Marseille, France., Department of Pediatrics, Academic Medical Center/Emma Pediatric Hospital, Amsterdam, The Netherlands.

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 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. 

Retracted: No

PubPeer comments:
 Could the authors pin point which nuclei have irregular shapes? The presented picture is not easy to appreciate the difference claimed by the authors.  , 
 The same scale bar (50uM) between all three panels in figure 7B? The nuclei of the right panel is smaller than the others, but no description in the text.  , 
  The figure legend says that scale bar = 50uM for each panel. Though the scale bar of E55G (right panel) looks differ from others. 100uM? , 
 We have received the following report relating to the above comment; readers may find it useful:  This comment has already been posted before and lately removed by the PubPeer admin. There is no foundation in the claim as it is easy to observe nuclei with a similar size in the three panels, which demonstrates that the scale bar is the same. The panel on the right, belonging to a patient with progeria show some heterogeneity in the nucleus size distribution, but it is related with the disease and properly cited on the manuscript. Please consider this post for removal and prevent this from happening again in the future. ,