Mutation in KERA Identified by Linkage Analysis and Targeted Resequencing in a Pedigree with Premature Atherosclerosis

Abstract

AimsGenetic 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.Methods and ResultsParametric 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).ConclusionA 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.

A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis

“…So far, mutations in Low Density Lipoprotein receptor (LDLR), Low-Density Lipoprotein Receptor Related Protein 6 (LRP6) and Myocyte Enhancer Factor 2 A (MEF2A), Keratocan (KERA), Guanylyl Cyclase α1 subunit (GUCY1A3) and Chaperonin Containing TCP1, Subunit 7 (CCT7) have been published, although conflicting results have been reported for MEF2A. [7][8][9][10][11][12][13][14][15] Collectively, the identification of informative pedigrees with a dominant form of premature CVD have proven to be instrumental in the identification of novel variants in genes involved in the pathobiology of CVD, which may ultimately result in the new therapeutic targets.…”

Evaluation of a large-scale aptamer proteomics platform among patients with kidney failure on dialysis

“…Epidemiological studies, human genetics and animal studies support its role in the development of atherosclerosis [ 31 ]. Keratocan maintains the extracellular matrix, and rare genetic variants have been associated with premature atherosclerosis [ 32 ]. Among those present at lower concentrations in participants who died, transketolase may promote cardiomyocyte apoptosis and play a role in ischemic heart failure [ 33 ].…”

The identification and function of a Netrin-1 mutation in a pedigree with premature atherosclerosis

“…Genomic DNA extraction, whole exome sequencing and candidate variant selection were done as previously described [17]. Based on a PubMed search, variants were appointed as being athero-associated or not (Supplemental Table 1).…”

“…In these studies, 10% of the total CVD risk is attributed to common genetic variations, which suggests that low frequency variants are likely to play a role in the so-called 'missed heritability' [48,49]. Family studies have been proven to be extremely instrumental to investigate this and identified culprit genetic defects in families with extreme phenotypes [17,50,51]. Therefore, we have taken our pedigree as a model to study Netrin-1 in great detail.…”