Distinct phenotypic features and gender-specific disease manifestations in a Spanish family with desmin L370P mutation

Arias, M; Pardo, Julio; Blanco-Arias, Patricia; Sobrido, María-Jesús; Arias, Susana; Dapena, D; Carracedo, Ángel; Goldfarb, Lev G.; Navarro, Carmen

doi:10.1016/j.nmd.2006.05.011

Cited by 26 publications

(18 citation statements)

References 26 publications

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“…miRNA-CNV frequency bias was observed on the CNV transmissions from maternal genome only, showing major contributions from deletion CNVs than duplications. We believe the existence of such biased transmissions greatly signifies the role of parental transmission in gene regulation and counters some distinct phenotypic features observed in previous studies [55]–[56] and in certain gender-specific disease manifestations.…”

Section: Discussionsupporting

confidence: 52%

Copy Number Variations Burden on miRNA Genes Reveals Layers of Complexities Involved in the Regulation of Pathways and Phenotypic Expression

Veerappa

Vishweswaraiah

et al. 2014

PLoS ONE

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MicroRNAs are involved in post-transcriptional down-regulation of gene expression. Variations in miRNA genes can severely affect downstream-regulated genes and their pathways. However, population-specific burden of CNVs on miRNA genes and the complexities created towards the phenotype is not known. From a total of 44109 CNVs investigated from 1715 individuals across 12 populations using high-throughput arrays, 4007 miRNA-CNVs (∼9%) consisting 6542 (∼5%) miRNA genes with a total of 333 (∼5%) singleton miRNA genes were identified. We found miRNA-CNVs across the genomes of individuals showing multiple hits in many targets, co-regulated under the same pathway. This study proposes four mechanisms unraveling the many complexities in miRNA genes, targets and co-regulated miRNA genes towards establishment of phenotypic diversity.

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Section: Discussionsupporting

confidence: 52%

Copy Number Variations Burden on miRNA Genes Reveals Layers of Complexities Involved in the Regulation of Pathways and Phenotypic Expression

Veerappa

Vishweswaraiah

et al. 2014

PLoS ONE

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“…Only three of six female patients had cardiac involvement, and this was much milder than in men. This correlates with data on a 10-member family carrying DES p.Leu370Pro mutation in which the males had a higher incidence of cardiomyopathy and cardiac arrhythmia resulting in sudden death by the end of the fourth decade of life while the female patients had a slow progression of illness limited to skeletal muscles [20]. A frequently discussed controversy that the DES p.Ile451Met mutation causes DCM/no skeletal myopathy in one family [21], but this same mutation causes progressive skeletal myopathy/no cardiomyopathy in another family [22] can now be solved considering the fact that only male patients were represented in the first family and only females have been studied in the second.…”

Section: Discussionsupporting

confidence: 85%

Clinical and Myopathological Characteristics of Desminopathy Caused by a Mutation in Desmin Tail Domain

Maddison

Damian²,

Sewry³

et al. 2012

Eur Neurol

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Background: Most of the previously described pathogenic mutations in desmin are located in highly conserved α-helical domains that play an important role in intermediate filament assembly. The role of the C-terminus non-α-helical ‘tail’ domain is much less investigated and until recently mutations in this domain have been implicated in only a few patients. The majority of reported desminopathy cases caused by the tail mutations were sporadic, creating a representation bias regarding the disease frequency and phenotypic characteristics. Methods: We performed detailed genotype-phenotype analysis of autosomal dominant desminopathy associated with tail domain mutations in a four-generation autosomal dominant family with 16 members affected by a progressive cardiac and/or skeletal myopathy caused by a c.1346A>C (p.Lys449Thr) mutation located in the tail domain of desmin. Results: Phenotypic features in patients with tail domain mutations are similar to those in patients with mutations localized in the 1B and 2B α-helical domains. Conclusion: We recommend that the tail domain is searched for mutations as intensely as desmin coil domains which until recently were considered to be more ‘functional’.

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“…Desminopathies have been reported in diverse ethnic groups and affect both female and male patients. Gender effects have been reported in two studies, in which male heterozygous mutation carriers were more prone to cardiac disease manifestations [5, 183]. The disease manifestation is highly variable with an age of onset ranging from the 1st to the 8th decade of life.…”

Section: Clinical Phenotypesmentioning

confidence: 99%

Desminopathies: pathology and mechanisms

et al. 2012

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The intermediate filament protein desmin is an essential component of the extra-sarcomeric cytoskeleton in muscle cells. This three-dimensional filamentous framework exerts central roles in the structural and functional alignment and anchorage of myofibrils, the positioning of cell organelles and signaling events. Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive, and sporadic myopathies and/or cardiomyopathies with marked phenotypic variability. The disease onset ranges from childhood to late adulthood. The clinical course is progressive and no specific treatment is currently available for this severely disabling disease. The muscle pathology is characterized by desmin-positive protein aggregates and degenerative changes of the myofibrillar apparatus. The molecular pathophysiology of desminopathies is a complex, multilevel issue. In addition to direct effects on the formation and maintenance of the extra-sarcomeric intermediate filament network, mutant desmin affects essential protein interactions, cell signaling cascades, mitochondrial functions, and protein quality control mechanisms. This review summarizes the currently available data on the epidemiology, clinical phenotypes, myopathology, and genetics of desminopathies. In addition, this work provides an overview on the expression, filament formation processes, biomechanical properties, post-translational modifications, interaction partners, subcellular localization, and functions of wild-type and mutant desmin as well as desmin-related cell and animal models.

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Distinct phenotypic features and gender-specific disease manifestations in a Spanish family with desmin L370P mutation

Cited by 26 publications

References 26 publications

Copy Number Variations Burden on miRNA Genes Reveals Layers of Complexities Involved in the Regulation of Pathways and Phenotypic Expression

Copy Number Variations Burden on miRNA Genes Reveals Layers of Complexities Involved in the Regulation of Pathways and Phenotypic Expression

Clinical and Myopathological Characteristics of Desminopathy Caused by a Mutation in Desmin Tail Domain

Desminopathies: pathology and mechanisms

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