Dataset Information

Novel mutations in LMNA A/C gene and associated phenotypes.

ABSTRACT: Mutations in the lamin A/C gene (LMNA) have been associated with several phenotypes ranging from systemic to prevalent of muscle, heart, skin, nerve etc. More recently they have been associated with dilated cardiomyopathy (DCM) and severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). We report four novel mutations - 3 missense and 1 deletion - in 4 unrelated patients showing different phenotypes, ranging from the early onset congenital form of laminopathy to classical LGMD phenotype, to LGMD and heart involvement. All these newly identified variants were not found in 300 ethnicallymatched control subjects. The variant c.103-105del CTG was described post-mortem in a young patient with congenital muscular dystrophy who presented at the age of 9 a first degree A-V block and subsequently several episodes of supraventricular parossystic tachycardia. Two patients presented as onset symptom lower limbs muscle weakness, and developed heart conduction defects requiring pacemaker implantation at the age of 26 and 38 years, respectively. One of them who carried the mutation c.1339G>C died at the age of 40 by intractable heart failure; the second one carrying the mutation 265C>T died at the age of 30, for a trmboembolic event. A classical LGMD phenotype without heart involvement was observed in the patient with the mutation 1579C>T, who died at the age of 68 years for respiratory insufficiency.

SUBMITTER: Petillo R

PROVIDER: S-EPMC4859074 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Novel mutations in LMNA A/C gene and associated phenotypes.

Petillo Roberta R D'Ambrosio Paola P Torella Annalaura A Taglia Antonella A Picillo Esther E Testori Alessandro A Ergoli Manuela M Nigro Gerardo G Piluso Giulio G Nigro Vincenzo V Politano Luisa L

Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 20151201 2-3

Mutations in the lamin A/C gene (LMNA) have been associated with several phenotypes ranging from systemic to prevalent of muscle, heart, skin, nerve etc. More recently they have been associated with dilated cardiomyopathy (DCM) and severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). We report four novel mutations - 3 missense and 1 deletion - in 4 unrelated patients showing different phenotypes, ranging from the early onset congenital form of laminopathy to classical LGMD phe ...[more]

PMID: 27199538

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Project description:BackgroundGoltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants.ResultsWe report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes.ConclusionsOur combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.

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Novel mutations in LMNA A/C gene and associated phenotypes.

Publications

Novel mutations in LMNA A/C gene and associated phenotypes.

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