TY - JOUR
T1 - 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
AU - Florwick, Alyssa
AU - Dharmaraj, Tejas
AU - Jurgens, Julie
AU - Valle, David
AU - Wilson, Katherine L.
N1 - Funding Information:
We gratefully acknowledge funding from the Progeria Research Foundation (PRF 2013-47) and the Johns Hopkins University Claude D. Pepper Older Americans Independence Center National Institutes of Health, National Institute on Aging (NIA P30AG021334) to KW, the Predoctoral Training Program in Human Genetics at Johns Hopkins University School of Medicine (NIH training grant T32GM07814) and Visual Neuroscience Training Program (NEI grant 2T32EY007143-21) to JJ, and the Baylor-Hopkins Center for Mendelian Genomics (NHGRI grant 1U54HG006542) to DV.
Publisher Copyright:
© 2017 Florwick, Dharmaraj, Jurgens, Valle and Wilson.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - African American
KW - Dilated cardiomyopathy
KW - ExAC
KW - FPLD2
KW - Latino
KW - Metabolic syndrome
KW - Progeria
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85021186691&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021186691&partnerID=8YFLogxK
U2 - 10.3389/fgene.2017.00079
DO - 10.3389/fgene.2017.00079
M3 - Article
C2 - 28663758
AN - SCOPUS:85021186691
SN - 1664-8021
VL - 8
JO - Frontiers in Genetics
JF - Frontiers in Genetics
IS - JUN
M1 - 79
ER -