Abstract
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.
Highlights
LMNA (MIM 150330) encodes two abundant proteins, lamins A and C, which are derived from alternative spliceforms of LMNA (Gruenbaum and Foisner, 2015) and form separate nuclear intermediate filaments important for nuclear structure, mechanical integrity and tissue-specific genome organization and signaling (Dauer and Worman, 2009; Burke and Stewart, 2014; Dialynas et al, 2015; Mattout et al, 2015; OsmanagicMyers et al, 2015; Perovanovic et al, 2016; Le Dour et al, 2017)
The resulting LMNA missense variants were all rare with allele frequencies ranging from 1-per-100,000 to 1-per-1,000, and were primarily heterozygous as expected
One general conclusion is that the ExAC cohort included
Summary
LMNA (MIM 150330) encodes two abundant proteins, lamins A and C, which are derived from alternative spliceforms of LMNA (Gruenbaum and Foisner, 2015) and form separate nuclear intermediate filaments important for nuclear structure, mechanical integrity and tissue-specific genome organization and signaling (Dauer and Worman, 2009; Burke and Stewart, 2014; Dialynas et al, 2015; Mattout et al, 2015; OsmanagicMyers et al, 2015; Perovanovic et al, 2016; Le Dour et al, 2017). Mutations in LMNA cause at least eight autosomal dominant phenotypes and five autosomal recessive phenotypes, termed laminopathies (Bonne et al, 1999; Bertrand et al, 2011). These include Emery-Dreifuss Muscular Dystrophy (EDMD2, MIM 181350; EDMD3, MIM 616516), dilated cardiomyopathy (DCM; MIM 115200), congenital muscular dystrophy (CMD; MIM 613205), limb-girdle muscular dystrophy (LGMD; MIM 159001), Charcot-Marie-Tooth disease (CMT2B1; MIM 605588), arthropathy, tendinous calcinosis, and progeroid syndrome (ATCP; Van Esch et al, 2006), familial partial lipodystrophy type 2 (FPLD2; MIM 151660), insulin resistance syndrome (IRS; Young et al, 2005), mandibuloacral dysplasia type A (MADA; MIM 248370) and Hutchinson-Gilford Progeria Syndrome (HGPS; MIM 176670). The heterogeneity of metabolic phenotypes caused by LMNA mutations (Lewandowski et al, 2015; Chan et al, 2016) motivated us to assess the frequency of LMNA missense variants in broad populations and evaluate their potential to influence disease risk
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