TY - JOUR
T1 - Mutation in KERA identified by linkage analysis and targeted resequencing in a pedigree with premature atherosclerosis
AU - Maiwald, Stephanie
AU - Sivapalaratnam, Suthesh
AU - Motazacker, Mahdi M.
AU - van Capelleveen, Julian C.
AU - Bot, Ilze
AU - de Jager, Saskia C.
AU - van Eck, Miranda
AU - Jolley, Jennifer
AU - Kuiper, Johan
AU - Stephens, Jonathon
AU - Albers, Cornelius A.
AU - Vosmeer, C. Ruben
AU - Kruize, Heleen
AU - Geerke, Daan P.
AU - van der Wal, Allard C.
AU - van der Loos, Chris M.
AU - Kastelein, John J. P.
AU - Trip, Mieke D.
AU - Ouwehand, Willem H.
AU - Dallinga-Thie, Geesje M.
AU - Hovingh, G. Kees
PY - 2014/5/30
Y1 - 2014/5/30
N2 - Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis. Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c.920C>G; p.Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe-/- mice (r2 = 0.69; p <0.0001). A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis
AB - Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis. Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c.920C>G; p.Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe-/- mice (r2 = 0.69; p <0.0001). A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis
U2 - https://doi.org/10.1371/journal.pone.0098289
DO - https://doi.org/10.1371/journal.pone.0098289
M3 - Article
C2 - 24879339
SN - 1932-6203
VL - 9
SP - e98289
JO - PLOS ONE
JF - PLOS ONE
IS - 5
ER -