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Gene analysis of the lamin A/C gene ( LMNA ). Sequencing of LMNA in our patient shows a heterozygous nonsense mutation (Q353X) in exon 6 (a). Structure of lamin A and the positions of mutations in various laminopathies are shown (b). For spinal muscular atrophy (SMA) phenotype, two of three mutations are located in the rod domain ( 6 and this report). Diamonds indicate the mutations positions of laminopathies. The rod domain of lamin A is a hot spot for neuromuscular and cardiac diseases such as Charcot-Marie-Tooth disease type 2B1 (CMT2B1), dilated cardiomyopathy (DCM), Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy (LGMD).
Source publication
Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A...
Contexts in source publication
Context 1
... genetic analysis was limited to the proband, as we could not get a permission from other family members. gene, and a novel nonsense mutation p.Q353X (c.1057C > T) in exon 6 of LMNA was detected (Figure 3a). Exon 6 encodes the rod domain of lamin A and lamin C, which results in truncated lamin A protein lacking tail domain including nuclear localization signal (NLS) site (Figure 3b). ...
Context 2
... and a novel nonsense mutation p.Q353X (c.1057C > T) in exon 6 of LMNA was detected (Figure 3a). Exon 6 encodes the rod domain of lamin A and lamin C, which results in truncated lamin A protein lacking tail domain including nuclear localization signal (NLS) site (Figure 3b). The genetic analysis was limited to the proband, as we could not get a permission from other family members. ...
Context 3
... clinical presentations were similar to previous cases family especially in cardiopathy, however, the gait disturbance were shown in different age. He had a novel nonsense mutation p.Q353X (c.1057C > T) in exon 6 of LMNA (Figure 3). In general, nonsense mutation in coding exon results in a significant molecular functional defect even with heterogeneity. ...
Context 4
... disorders are called laminopathies, and they include autosomal dominant Emery-Dreifuss muscular dystrophy (EMDM), autosomal repressive EMDM, Limb-girdle muscular dystrophy 1B (LGMD1B), Dilated cardiomyopathy with conduction defects (CMD1A), and CMT type 2B1 (CMT2B1). Laminopathies involving the muscular system and the peripheral nervous system both of which have mutations mainly at the N-terminal side of the NLS (Figure 3b). These diseases are suspected to result from abnormalities of the nuclear laminar struc- ture. ...
Citations
... Mutations affecting both lamin and desmin (type V and type III intermediate filament proteins, respectively), commonly give rise to conditions associated with cardiomyopathy and heart failure (25). Of additional relevance is that mutations in LMNA -the lamin A/C gene-have been attributed to adult-onset conditions with an SMA-like phenotype (26,27). Lamin A was identified by iTRAQ as being increased in both the Taiwanese (15) and Smn 2B/− SMA mouse models (Supplementary Material, Table S1) (albeit it just missed the criteria for differential expression in the Smn 2B/− with p = 0.056). ...
... In terms of impact on heart conditions and development of dilated cardiomyopathy, impairment of the lamin A/C gene is a well-known factor (50) and results in conduction problems, arrhythmias, atrioventricular block and sudden cardiac death (51)(52)(53)(54)(55) with at least 260 LMNA mutations having been linked to cardiac diseases (56). In several studies, LMNA mutations have also resulted in an SMA-like phenotype with cardiac involvement (26,27). ...
Structural, functional and molecular cardiac defects have been reported in spinal muscular atrophy (SMA) patients and mouse models. Previous quantitative proteomics analyses demonstrated widespread molecular defects in the severe Taiwanese SMA mouse model. Whether such changes are conserved across different mouse models, including less severe forms of the disease, has yet to be established. Here, using the same high-resolution proteomics approach in the less-severe Smn2B/- SMA mouse model, 277 proteins were found to be differentially abundant at a symptomatic timepoint (post-natal day (P) 18), 50 of which were similarly dysregulated in severe Taiwanese SMA mice. Bioinformatics analysis linked many of the differentially abundant proteins to cardiovascular development and function, with intermediate filaments highlighted as an enriched cellular compartment in both datasets. Lamin A/C was increased in cardiac tissue whilst another intermediate filament protein, desmin, was reduced. The extracellular matrix (ECM) protein, elastin, was also robustly decreased in the heart of Smn2B/- mice. AAV9-SMN1-mediated gene therapy rectified low levels of survival motor neuron (SMN) protein and restored desmin levels in heart tissues of Smn2B/- mice. In contrast AAV9-SMN1 therapy failed to correct lamin A/C or elastin levels. Intermediate filament proteins and the ECM have key roles in cardiac function and their dysregulation may explain cardiac impairment in SMA, especially since mutations in genes encoding these proteins cause other diseases with cardiac aberration. Cardiac pathology may need to be considered in the long-term care of SMA patients, as it is unclear whether currently available treatments can fully rescue peripheral pathology in SMA.
... Needle EMG includes mixed chronic denervation and reinnervation findings and mild myopathic features, while targetoid-fibers and type grouping are commonly observed in muscle biopsy. More than 10 different allelic clinical conditions have been described, including autosomal dominant or recessive Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy type 1B, Hutchinson-Gilford progeria, CMT type 2B1, and different syndromic and non-syndromic restrictive or dilated cardiomyopathies 11,52,53 . ...
Background:
Adult-onset spinal muscular atrophy (SMA) represents an expanding group of inherited neurodegenerative disorders in clinical practice.
Objective:
This review aims to synthesize the main clinical, genetic, radiological, biochemical, and neurophysiological aspects related to the classical and recently described forms of proximal SMA.
Methods:
The authors performed a non-systematic critical review summarizing adult-onset proximal SMA presentations.
Results:
Previously limited to cases of SMN1-related SMA type 4 (adult form), this group has now more than 15 different clinical conditions that have in common the symmetrical and progressive compromise of lower motor neurons starting in adulthood or elderly stage. New clinical and genetic subtypes of adult-onset proximal SMA have been recognized and are currently target of wide neuroradiological, pathological, and genetic studies.
Conclusions:
This new complex group of rare disorders typically present with lower motor neuron disease in association with other neurological or systemic signs of impairment, which are relatively specific and typical for each genetic subtype.
... Moreover, mutations in the same gene can also lead to different forms of phenotype abnormity. For example, mutations in lamin A/C (LMNA) gene can result in Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy [7]. The complicated genetic and phenotypic heterogeneity poses substantial obstacles to a rapid and accurate diagnosis in the conventional workup, and makes patients embark on a "diagnostic odyssey". ...
Background
Due to large genetic and phenotypic heterogeneity, the conventional workup for Charcot-Marie-Tooth (CMT) diagnosis is often underpowered, leading to diagnostic delay or even lack of diagnosis. In the present study, we explored how bioinformatics analysis on whole-exome sequencing (WES) data can be used to diagnose patients with CMT disease efficiently.
Case presentation
The proband is a 29-year-old female presented with a severe amyotrophy and distal skeletal deformity that plagued her family for over 20 years since she was 5-year-old. No other aberrant symptoms were detected in her speaking, hearing, vision, and intelligence. Similar symptoms manifested in her younger brother, while her parents and her older brother showed normal. To uncover the genetic causes of this disease, we performed exome sequencing for the proband and her parents. Subsequent bioinformatics analysis on the KGGSeq platform and further Sanger sequencing identified a novel homozygous GDAP1 nonsense mutation (c.218C > G, p.Ser73*) that responsible for the family. This genetic finding then led to a quick diagnosis of CMT type 4A (CMT4A), confirmed by nerve conduction velocity and electromyography examination of the patients.
Conclusions
The patients with severe muscle atrophy and distal skeletal deformity were caused by a novel homozygous nonsense mutation in GDAP1 (c.218C > G, p.Ser73*), and were diagnosed as CMT4A finally. This study expanded the mutation spectrum of CMT disease and demonstrated how affordable WES could be effectively employed for the clinical diagnosis of unexplained phenotypes.
... In this study, we have conducted a comprehensive quantitative proteomics analysis of heart tissue from the Taiwanese mouse model of severe SMA and show that there is widespread dysregulation of protein expression in SMA compared to controls. We verified the robust increase of one of these proteins, lamin A/C, in the hearts of SMA mice, and propose a role for lamin A/C in SMA cardiac pathology, strongly supported by case reports of an adult form of SMA caused by mutations in the lamin A/C encoding gene, LMNA (17,18). As with a wide range of neuromuscular conditions caused by mutations in LMNA, including Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy 1B, and dilated cardiomyopathy, cardiac involvement was a notable feature in each case of LMNA-associated SMA. ...
... One of the 383 differentially expressed proteins, lamin A/C, was of particular interest to us since mutations in LMNA, the lamin A/C encoding gene, are known to cause an adult form of SMA (17,18). Additionally, the analysis of published proteomic studies of the neuromuscular system in SMA (26) identified lamin A/C as a conserved molecular change across three separate studies of SMA (27)(28)(29). ...
... A small percentage of SMA cases are associated with mutations in genes other than SMN, including UBA1 (34), glycyl-tRNA synthetase 1 (GARS1) (35) and LMNA (17,18). Mutations in the UBA1 gene, which encodes the UBA1 protein, cause a form of X-linked infantile SMA (spinal muscular atrophy, x-linked 2) (34), and a role for UBA1 in SMN-dependent pathways has also been well characterized across several models of SMA (19)(20)(21). ...
Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice, and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in-vitro by knockdown of the E1 ubiquitination factor UBA1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signalling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.
... These include an individual who was a compound heterozygote for the R527H and V440M LMNA mutations, and showed some signs of mandibuloacral dysplasia as well as muscular involvement [106]. These two LMNA mutations could explain the patient's two apparently unrelated phenotypes [107]; and that of a 65-year-old man with the novel nonsense mutation p.Q353X, who presented with amyotrophy of the lower limbs, arrhythmia and cardiac hypofunction, and neurological and electrophysiological alterations, suggesting spinal muscular atrophy type 3 [108]. ...
The biggest challenge geneticists face when applying next-generation sequencing technology to the diagnosis of rare diseases is determining which rare variants, from the dozens or hundreds detected, are potentially implicated in the patient’s phenotype. Thus, variant prioritization is an essential step in the process of rare disease diagnosis. In addition to conducting the usual in-silico analyses to predict variant pathogenicity (based on nucleotide/amino-acid conservation and the differences between the physicochemical features of the amino-acid change), three important concepts should be borne in mind. The first is the “mutation tolerance” of the genes in which variants are located. This describes the susceptibility of a given gene to any functional mutation and depends on the strength of purifying selection acting against it. The second is the “mutational architecture” of each gene. This describes the type and location of mutations previously identified in the gene, and their association with different phenotypes or degrees of severity. The third is the mode of inheritance (inherited vs. de novo) of the variants detected. Here, we discuss the importance of each of these concepts for variant prioritization in the diagnosis of rare diseases. Using real data, we show how genes, rather than variants, can be prioritized by calculating a gene-specific mutation tolerance score. We also illustrate the influence of mutational architecture on variant prioritization using five paradigmatic examples. Finally, we discuss the importance of familial variant analysis as final step in variant prioritization.
... NCAM, a known regulator of neuronal growth, has been described in connection with different neurological disorders and seems to be an interesting target for further studies in relation to SMA phenotype modification [185]. Mutations in LMNA, a published interactor of SMN, were shown to be involved in the development of muscular dystrophies and mimic spinal muscular atrophy [186,187]. ...
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the SMN1 gene. Being a monogenic disease, it is characterized by high clinical heterogeneity. Variations in penetrance and severity of symptoms, as well as clinical discrepancies between affected family members can result from modifier genes influence on disease manifestation. SMN2 gene copy number is known to be the main phenotype modifier and there is growing evidence of additional factors contributing to SMA severity. Potential modifiers of spinal muscular atrophy can be found among the wide variety of different factors, such as multiple proteins interacting with SMN or promoting motor neuron survival, epigenetic modifications, transcriptional or splicing factors influencing SMN2 expression. Study of these factors enables to reveal mechanisms underlying SMA pathology and can
have pronounced clinical application.
... In our study, we examined and analyzed the aberrations of the nuclear lamina and chromosomes in skin fibroblasts of patients with 3 different forms of CS (severe, atypical, and severe and light). [8,9] Multiprotein complexes involved in cell development can regulate gene activity at various stages of the transcription process. Results of many works show the important role of nuclear positioning in the control of gene expression where nuclear envelope components play a central role. ...
Rationale:
Postnatal growth failure and progressive neurologic dysfunction and increasing multiorgan involvement are the main clinical features of Cockayne syndrome (CS). CS is a rare autosomal recessive disorder of the group of DNA repair diseases. Usually, genetic carriers, such as parents of patients, are not at risk for developing the disease.
Patient concerns:
A series of 14 family subjects (6 children with age range from 6 months to 4 years with CS) and 9 parents (aged from 23 to 34 years) from consanguineous families is reported.
Diagnoses:
Ultraviolet irradiation studies were performed on these children and were indicative of CS.
Interventions:
Cells of skin fibroblast from these children with the disease showed a symmetrical accumulation of chromosomal aberrations and the nuclear lamina aberrations. Our results showed a significant and simultaneous increase of percent of blebbs and invaginations of the nuclear lamina in all cases CS. The pronounced changes in 12.6 times at atypical form (girl); in 8.5 times at severe form (boy) and in 5.6 times at light form (boy). Percentage of metaphases with chromosomal aberration is significantly higher in CS cells: in 4 times at atypical form, in 3 times at hard form, and in 2 times at light form. The parents of these families (consanguineous families) were intellectually variable between normal/borderline intelligence, though most manifested a constellation of skeletal and extraskeletal abnormalities and notably, the characteristic cachectic facial appearance. The parents were considered as manifesting the mild type of CS, because they showed no abnormalities of DNA repair.
Outcomes:
Clinical manifestations in heterozygote carriers of an autosomal recessive disorders is a rare phenomenon as carriers are usually healthy.
Lessons:
The interesting finding of the families studied is that there appeared to be a multitude of carriers manifesting with normal to borderline intelligence but with a wide spectrum of skeletal and extraskeletal abnormalities.
... Besides the already mentioned case of ARVC, a first linkage between a lamin A/C gene mutation and spinal muscular atrophy (SMA) in the autosomal dominant form has been demonstrated by Rudnik-Sch€ oneborn et al. (2007). SMA phenotype and LMNA mutation have been recently associated again, in the study of Iwahara et al. (2015), hence confirming the previous findings. ...
In the last decades, atomic force microscopy (AFM) underwent a rapid and stunning development, especially for studying mechanical properties of biological samples. The numerous discoveries relying to this approach, have increased the credit of AFM as a versatile tool, and potentially eligible as a diagnostic equipment. Meanwhile, it has become strikingly evident that lamins are involved on the onset and development of certain diseases, including cancer, Hutchinson-Gilford progeria syndrome, cardiovascular pathologies, and muscular dystrophy. A new category of pathologies has been defined, the laminopathies, which are caused by mutations in the gene encoding for A-type lamins. As the majority of medical issues, lamins, and all their related aspects can be considered as a quite complex problem. Indeed, there are many facets to explore, and this definitely requires a multidisciplinary approach. One of the most intriguing aspects concerning lamins is their remarkable contribute to cells mechanics. Over the years, this has led to the speculation of the so-called "structural hypothesis", which attempts to elucidate the etiology and some features of the laminopathies. Among the various techniques tried to figure out the role of lamins in the cells mechanics, the AFM has been already successfully applied, proving its versatility. Therefore, the present work aims both to highlight the qualities of AFM and to review the most relevant knowledge about lamins, in order to promote the study of the latter, taking advantage from the former.
... Mutations in LMNA cause a range of disorders, including muscular dystrophies such as Charcot-Marie-Tooth disease and Emery-Dreifuss muscular dystrophy [62]. Given that mutations in the LMNA gene can cause an SMA phenotype [27,28], it is surprising that further studies to explore the relationship between LMNA and SMA have not been pursued. ...
The neuromuscular disease spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting from low levels of full-length survival motor neuron (SMN) protein. Despite having a good understanding of the underlying genetics of SMA, the molecular pathways downstream of SMN that regulate disease pathogenesis remain unclear. The identification of molecular perturbations downstream of SMN is required in order to fully understand the fundamental biological role(s) for SMN in cells and tissues of the body, as well as to develop a range of therapeutic targets for developing novel treatments for SMA. Recent developments in proteomic screening technologies have facilitated proteome-wide investigations of a range of SMA models and tissues, generating novel insights into disease mechanisms by highlighting conserved changes in a range of molecular pathways. Comparative analysis of distinct proteomic datasets reveals conserved changes in pathways converging on GAP43, GAPDH, NCAM, UBA1, LMNA, ANXA2 and COL6A3. Proteomic studies therefore represent a leading tool with which to dissect the molecular mechanisms of disease pathogenesis in SMA, serving to identify potentially attractive targets for the development of novel therapies.
... The case of a patient with a SMA phenotype due to a LMNA mutation who also developed arrhythmias and systolic dysfunction has been reported. 8) CI in amyotrophic lateral sclerosis (ALS) can present with dCMP, 9) cardiac sympathetic hyperactivity, 10) arrhythmias, 11) or TTS ( Table 2). 12) Admittedly, the diagnosis of ALS was not definitively determined in a subset of these cases. ...
Little is known regarding cardiac involvement (CI) by neuromuscular disorders (NMDs). The purpose of this review is to summarise and discuss the major findings concerning the types, frequency, and severity of cardiac disorders in NMDs as well as their diagnosis, treatment, and overall outcome. CI in NMDs is characterized by pathologic involvement of the myocardium or cardiac conduction system. Less commonly, additional critical anatomic structures, such as the valves, coronary arteries, endocardium, pericardium, and even the aortic root may be involved. Involvement of the myocardium manifests most frequently as hypertrophic or dilated cardiomyopathy and less frequently as restrictive cardiomyopathy, non-compaction, arrhythmogenic right-ventricular dysplasia, or Takotsubo-syndrome. Cardiac conduction defects and supraventricular and ventricular arrhythmias are common cardiac manifestations of NMDs. Arrhythmias may evolve into life-threatening ventricular tachycardias, asystole, or even sudden cardiac death. CI is common and carries great prognostic significance on the outcome of dystrophinopathies, laminopathies, desminopathies, nemaline myopathy, myotonias, metabolic myopathies, Danon disease, and Barth-syndrome. The diagnosis and treatment of CI in NMDs follows established guidelines for the management of cardiac disease, but cardiotoxic medications should be avoided. CI in NMDs is relatively common and requires complete work-up following the establishment of a neurological diagnosis. Appropriate cardiac treatment significantly improves the overall long-term outcome of NMDs.
