Autosomal recessive <i>LMNA</i> mutation causing Restrictive Dermopathy

Youn, GJ; Uzunyan, M; Vachon, Linda; Johnson, Jeremy; Winder, T.; Yano, Shoji

doi:10.1111/j.1399-0004.2010.01385.x

Cited by 14 publications

(13 citation statements)

References 4 publications

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“…However, the ExAC cohort included variants at three other progeria-relevant residues: R435, R471, and R527. One ExAC individual carried p.R435C (allele frequency 0.000863%); this variant is reported as heterozygous in 14 asymptomatic individuals in the laminopathy cohort and one DCM patient (Vytopil et al, 2003), and homozygously in single cases of progeria (Madej-Pilarczyk et al, 2009) or restrictive dermopathy (Youn et al, 2010). Three individuals in ExAC carried p.R471C (allele frequency 0.00256%); this variant is also reported in the laminopathy cohort in three asymptomatic heterozygous individuals, one homozygous patient with MADA/progeria (Zirn et al, 2008) and one HGPS patient in compound heterozygosity with p.R527C (Cao and Hegele, 2003).…”

Section: Resultsmentioning

confidence: 99%

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

et al. 2017

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Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases (‘laminopathies’) including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2), insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations (‘variants’) in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA). We identified 169 variants in the ExAC cohort, of which 37 (∼22%) are disease-associated including p.I299V (allele frequency 0.0402%), p.G602S (allele frequency 0.0262%) and p.R644C (allele frequency 0.124%), suggesting certain LMNA mutations are more common than previously recognized. Independent analysis of LMNA variants via the type 2 diabetes (T2D) Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (p = 0.02; odds ratio = 4.58), and was more frequent in African Americans (allele frequency 0.297%). The FPLD2-associated variant I299V was most prevalent in Latinos (allele frequency 0.347%). The ExAC cohort also revealed 132 novel LMNA missense variants including p.K108E (limited to individuals with psychiatric disease; predicted to perturb coil-1B), p.R397C and p.R427C (predicted to perturb filament biogenesis), p.G638R and p.N660D (predicted to perturb prelamin A processing), and numerous Ig-fold variants predicted to perturb phenotypically characteristic protein–protein interactions. Overall, this two-pronged strategy— mining a large database for missense variants in a single gene (LMNA), coupled to knowledge about the structure, biogenesis and functions of A-type lamins— revealed an unexpected number of LMNA variants, including novel variants predicted to perturb lamin assembly or function. Interestingly, this study also correlated novel variant p.K108E with psychiatric disease, identified known variant p.I299V as a potential risk factor for metabolic disease in Latinos, linked variant p.G602 with type 2 diabetes, and identified p.G602S as a predictor of diabetes risk in African Americans.

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Section: Resultsmentioning

confidence: 99%

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

et al. 2017

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“…Restrictive dermopathy (RD) is a rare lethal genetic disorder that is characterized by congenital tautness of the skin with associated fibrosis of the dermis [107,123]. This skin disorder has been linked to mutations in the lamin A gene and recent data suggest a relationship between lamin mutations and ROS accumulation via Nox4 [88].…”

Section: The Role Of Nox In Skin Fibrosismentioning

confidence: 99%

NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents

et al. 2013

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Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms that Nox enzymes influence specific skin fibrotic disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists.

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“…RD is a neonatal and lethal syndrome with severe intrauterine growth retardation, generalized arthrogryposis and tense skin, and clavicle osteolysis. Only three cases of RD are linked either to de novo heterozygous LMNA mutation, leading, as in HGPS, to in-frame partial or total deletion of exon 11, which lead to in-frame deletion of prelamin A that lacks its proteolytic cleavage site, stays abnormally farnesylated and accumulates in cells [27], or to a homozygous missense LMNA mutation [30]. In contrast, fatal fetal akinesia associates with multiple contractures, generalized muscular dystrophy with quasi absence of intercostal muscles, and is due to an homozygous nonsense LMNA mutation leading to the absence of A-type lamins, meaning that the total knockout of lamin A/C in human is lethal [29,31].…”

Section: Premature Aging Syndromesmentioning

confidence: 99%

Clinical and genetic heterogeneity in laminopathies

Bertrand

Chikhaoui

Yaou

et al. 2011

Biochemical Society Transactions

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Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability.

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Autosomal recessive LMNA mutation causing Restrictive Dermopathy

Cited by 14 publications

References 4 publications

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents

Clinical and genetic heterogeneity in laminopathies

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