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J Med Genet. 2016 Nov;53(11):776-785. doi: 10.1136/jmedgenet-2015-103695. Epub 2016 Jun 22.

Novel LMNA mutations cause an aggressive atypical neonatal progeria without progerin accumulation.

Author information

1
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
2
Servicio de Pediatría, Corporació Sanitària Parc Taulí, Sabadell, Spain.
3
Rehabilitation Center for Children and Adolescents, Pulderbos, Belgium.
4
Division of Human Genetics, UCT Faculty of Health Sciences, Cape Town, South Africa.
5
Department of Pediatrics Medi Clinic Hospital, Swakopmund, Namibia.
6
Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
7
Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
8
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.
9
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>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.

KEYWORDS:

HGPS; aging

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