Progeria caused by a rare LMNA mutation p.S143F associated with mild myopathy and atrial fibrillation

Madej-Pilarczyk, Agnieszka; Kmieć, Tomasz; Fidziańska, Anna; Rękawek, Joanna; Niebrój-Dobosz, I; Turska−Kmieć, Anna; Nestorowicz, Klaudia; Jóźwiak, Sergiusz; Hausmanowa-Pétrusewicz, I

doi:10.1016/j.ejpn.2007.11.011

Cited by 14 publications

(14 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Skeletal muscle dystrophy manifests itself with cardiac dysfunction abnormal gait, muscular atrophy with associated muscle weakness. The severity of the symptoms can extend into diagnostic regimes like defects in joint movement and contractures, muscle pain and wasting 50 .…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Dystrophy mutant of lamin A alters the structure and dynamics of the Ig fold domain

Dutta

Das

Maganti

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Mutations in the different domains of A-type lamin proteins cause a diverse plethora of diseases collectively termed as laminopathies which can affect multiple organs. Ig fold is one such domain of lamin A which is implicated in numerous nuclear interactions wherein the mutations lead to different laminopathies. W514R is one such mutation in the Ig fold which leads to severe phenotypes in Skeletal Muscle Dystrophy (SMD) which is a class of laminopathies. In this report, we elucidated gross alterations in structure and dynamics at the level of individual amino acids. These studies indicate altered conformational features of residues in the close vicinity of W514. Imaging of mammalian cells transfected with the mutant have shown distinct perturbation of the nuclear meshwork with concomitant alteration in nuclear interactions as a result of increased oligomerization of Ig W514R. Hence, this novel approach of amalgamating theoretical and experimental procedures to predict the severity of a mutant in the context of laminopathies could be extended for numerous lamin A mutants.

show abstract

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Dystrophy mutant of lamin A alters the structure and dynamics of the Ig fold domain

Dutta

Das

Maganti

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…38 As the diminished joint mobility observed in HGPS patients does not appear to be due to tightening of the skin, one may hypothesize that it may be due to muscle sclerosis and tightness similar to what is observed in myopathies. The emergence of LMNA gene mutations in HGPS patients prompted the examination of skeletal muscle, leading to the description of the first cases with progeroid syndrome and confirmed earlyonset myopathy due to p.Ser143Phe LMNA substitution 39,40 or type A MAD due to p.Arg471Cys homozygous 41 or p.Arg527His/Val440Met compound heterozygous 42 LMNA mutation. Among the 30 previously reported ZMPSTE24-mutated patients; none had an obvious or proven skeletal muscle involvement.…”

Section: Discussionmentioning

confidence: 99%

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

et al. 2011

View full text Add to dashboard Cite

Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T4C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general. Keywords: ZMPSTE24; mandibuloacral dysplasia; congenital myopathy; prelamin A; secondary laminopathies INTRODUCTION ZMPSTE24 (also known as FACE-1) encodes a ubiquitously expressed zinc metalloprotease. Prelamin A, the lamin A precursor, is the only known substrate of ZMPSTE24 in mammals. 1 ZMPSTE24 is involved in post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A. 2 Prelamin A is initially farnesylated on the last cysteine within the prenylation 'CaaX' motif at the C-terminus end of the protein by a farnesyltransferase. 3 Thereafter, ZMPSTE24 or RCE1 4 removes the last three residues 'aaX' , before a carboxy-methyl group is added by the methyl transferase ICMT on the last remaining cysteine. 5 Finally, a second cleavage is specifically carried out by ZMPSTE24, removing the last 15 amino acids. 6 The product of this post-translational maturation pathway, mature lamin A, is located both at the nuclear lamina and the nucleoplasm. A-type lamins A and C are expressed in all vertebrate differentiated cells, and are translated from alternatively spliced transcripts of the LMNA gene. After post-translational modifications,

show abstract

“…Patients with these mutations often have phenotypes overlapping between different progeroid syndromes or other laminopathies. 155,156 Finally, it is worth noting that lamin B1 has been linked to leukodystrophy 157 and lamin B2 to partial lipodystrophy, 158 though little is known about the pathogenic mechanism, and lamins have also been linked to cancer. In fact, loss of lamin A was one of the first historical biomarkers associated with increased metastasis; 159 however, the focus on this was dropped because such trends differed in different tumor types.…”

Section: Mutations In Nucleoskeletal Proteins Cause Human Diseasementioning

confidence: 99%

Nucleoskeleton dynamics and functions in health and disease

Meinke

Макаров

Thành

et al. 2015

CHC

View full text Add to dashboard Cite

It is a common misconception to view the "cyto"-skeleton as just the filament systems in the "cyto"-plasm. In fact, the cytoskeleton extends into the nucleus where the complex network connects to chromatin, and it also connects through the plasma membrane to the cytoskeleton of adjacent cells and to the "exo"-skeleton of the extracellular matrix. This review will focus principally on the subcomplex of the cytoskeleton associated with the nucleus, often referred to as the nucleoskeleton, but in the context of its extensive interconnectivity with the rest of the nucleus and with cytoplasmic filament systems all the way to the exoskeleton. The nucleoskeleton, made principally of type-V intermediate filament lamins, connects across the double membrane system of the nuclear envelope to likely all three primary cytoplasmic filament systems. It provides structural stability to the nucleus, and also incredible flexibility. In both its core structural aspect and through specificity gained by tissue-specific partner proteins, it contributes to genome organization and regulation as well as to signal transduction, both through chemical signaling cascades and likely through mechanotransduction. Defects in the nucleoskeleton have far-ranging effects due to its interactions with cytoplasmic filament systems, from mispositioning of nuclei to disruption of cell polarity and both decreased and increased cell migration depending on the defect. Accordingly, it is not surprising that many nucleoskeletal components are linked to a wide range of human diseases from specific types of cancer to muscular dystrophies, neuropathies, dermopathies, and premature aging syndromes.

show abstract

Progeria caused by a rare LMNA mutation p.S143F associated with mild myopathy and atrial fibrillation

Cited by 14 publications

References 16 publications

Skeletal Muscle Dystrophy mutant of lamin A alters the structure and dynamics of the Ig fold domain

Skeletal Muscle Dystrophy mutant of lamin A alters the structure and dynamics of the Ig fold domain

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

Nucleoskeleton dynamics and functions in health and disease

Contact Info

Product

Resources

About