AUTHOR=Florwick Alyssa , Dharmaraj Tejas , Jurgens Julie , Valle David , Wilson Katherine L. 

TITLE=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

JOURNAL=Frontiers in Genetics

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2017.00079

DOI=10.3389/fgene.2017.00079

ISSN=1664-8021

ABSTRACT=<p>Mutations in <italic>LMNA</italic>, 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 <italic>LMNA</italic> 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 <italic>LMNA</italic> mutations are more common than previously recognized. Independent analysis of <italic>LMNA</italic> variants via the type 2 diabetes (T2D) Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (<italic>p</italic> = 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 <italic>LMNA</italic> 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 (<italic>LMNA</italic>), coupled to knowledge about the structure, biogenesis and functions of A-type lamins— revealed an unexpected number of <italic>LMNA</italic> 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.</p>