Homozygous Lamin A/C familial lipodystrophy R482Q mutation in autosomal recessive Emery Dreifuss muscular dystrophy

Wiltshire, Katie; Hegele, Robert A.; Innes, A. Micheil; Brownell, A. Keith W.

doi:10.1016/j.nmd.2012.11.011

Cited by 27 publications

(11 citation statements)

References 12 publications

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“…Mutations in the human LMNA gene cause dysregulation of adipose tissue referred to as lipodystrophy (Wiltshire, Hegele, Innes & Brownell, 2013). These individuals experience age‐related loss of subcutaneous fat from their lower body and increased visceral fat in the upper portion of their body.…”

Section: Resultsmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

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Section: Resultsmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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“…The letter emphasizes that these are research results and should be clinically confirmed before being used to guide medical care or decision making. The letter also provides interpretation of all results, reviews autosomal recessive inheritance and risks, and emphasizes that the participant could still be a carrier for mutations causing any of the remaining autosomal recessive diseases that are segregating in this population (Armistead et al, 2009; Beaulieu et al, 2013; Bogershausen et al, 2013; Boycott et al, 2010; Boycott et al, 2008; Chong et al, 2012; Wiltshire, Hegele, Innes, & Brownell, 2013). The letter invites recipients to contact us by mail or phone with further questions and offers our assistance in arranging clinical confirmation of results.…”

Section: Educational Session and Disclosure Of Individual Research Resultsmentioning

confidence: 99%

“…The North American Hutterites are one of the best-characterized young founder populations (Boycott et al, 2008; Hostetler, 1974; Ober, Abney, & McPeek, 2001; Steinberg, Bleibtreu, Kurczynski, Martin, & Kurczynski, 1967), with more than 36 autosomal recessive (AR) diseases reported in members of this population (Beaulieu et al, 2013; Bogershausen et al, 2013; Boycott et al, 2010; Boycott et al, 2008; Caliskan et al, 2011; Gerull et al, 2013; Huang et al, 2011; Wiltshire, Hegele, Innes, & Brownell, 2013), such as Joubert syndrome, restrictive dermopathy, and nonsyndromic deafness. The Hutterites are an Anabaptist religious group that originated during the 1500s in the Tyrolean Alps.…”

Section: Introductionmentioning

confidence: 99%

Disclosure of Genetic Research Results to Members of a Founder Population

Anderson

Murray

Chong

et al. 2014

Journal of Genetic Counseling

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There is currently extensive discussion and debate in the literature on how, when, and to whom genetic research results should be returned (see Genetics in Medicine, April 2012 issue). Here, we describe our experience in disclosing genetic information on Mendelian disorders discovered during the course of our research in the Hutterites. We first assessed attitudes toward the disclosure of carrier results, which revealed that many individuals wanted carrier information and that many intended to use the information in family planning. Based on this information, we developed a pilot study to test and disclose cystic fibrosis (CF) carrier status. Next, a larger scale project was developed in order to disclose genetic research results for 14 diseases to those interested in receiving the information. We developed brochures, offered a live interactive educational program, conducted a consent process, and disclosed results in letters mailed to the consented individuals. Overall, ∼80% of individuals who participated in the educational program signed consent forms for the release of their results for 14 diseases. We describe our experience with returning individual genetic research results to participants in a population-based research study.

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“…All patients provided their written informed consent for genotyping. Since the previous publication of Wiltshire et al, 15 we have collected many new cases (4 homozygous and 17 heterozygous) diagnosed by their clinical presentation or because they were from families known to carry the mutation.…”

Section: Patient Populationmentioning

confidence: 99%

“…15 The phenotype is usually more severe than that observed in patients with Dunnigan syndrome associated with a heterozygous mutation.…”

Section: Introductionmentioning

confidence: 99%

Metabolic and cardiac phenotype characterization in 37 atypical Dunnigan patients with nonfarnesylated mutated prelamin A

André¹,

Schneebeli²,

Vigouroux³

et al. 2015

American Heart Journal

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Homozygous Lamin A/C familial lipodystrophy R482Q mutation in autosomal recessive Emery Dreifuss muscular dystrophy

Cited by 27 publications

References 12 publications

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Disclosure of Genetic Research Results to Members of a Founder Population

Metabolic and cardiac phenotype characterization in 37 atypical Dunnigan patients with nonfarnesylated mutated prelamin A

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