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.
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Contributors CS-V: performed experimental work, data interpretation and preparation of the manuscript. DC: performed experimental work and data interpretation. EG: performed medical writing for content. GV: developed sequencing work and data interpretation. VQ: participated in data interpretation and preparation of the manuscript CB: performed experimental work. MM: performed medical writing for content. KF, SM and MO: provided critical materials. DAP: developed sequencing work. OA: provided critical materials. BL: contributed to medical writing for content. AP: provided critical materials. VB: developed sequencing work. WW: performed medical writing for content. NL: provided critical materials. RCH: contributed to medical writing for content. ADSG: provided critical materials. CL-O: supervised research and project planning, data interpretation and preparation of the manuscript. All the authors drafted the work or revised it critically and gave final approval of the version to be published.
Funding This work was supported by grants from Ministerio de Economía y Competitividad-Spain (grant number SAF2014-52413-R), Gobierno del Principado de Asturias, Instituto de Salud Carlos III (RTICC), (grant number RD12/0036/0067) Spain, and EDP Foundation. We also thank the generous support by JI Cabrera. The Instituto Universitario de Oncología is supported by Fundación Bancaria Caja de Ahorros de Asturias. CL-O is an Investigator of the Botín Foundation supported by Banco Santander through its Santander Universities Global Division.
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval The medical ethics committee of the Hospital Universitario Central de Asturias, in compliance with the Helsinki Declaration.
Provenance and peer review Not commissioned; externally peer reviewed.