The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

Abstract

Aims/hypothesis: This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes. Methods: We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions. Results: We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, acounting for 5% of the variation in plasma insulin in elderly subjects. Conclusions/interpretation: Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.

PARL Leu262Val is not associated with fasting insulin levels in UK populations

“…In a dominant model, PARL genotype was associated with fasting plasma insulin levels and modified the positive association between age and fasting insulin. There was no statistically significant association between this variant and BMI [5].…”

“…The statistically significant association between genotype and fasting insulin reported by the original study was based on a US cohort with higher mean BMI than our UK cohorts [5]. In an exploratory analysis, we investigated the impact of BMI on the association between genotype and fasting insulin in the pooled dataset.…”

“…Nor were we able to replicate the genotype-age Data are means±SE, unless otherwise indicated The p value indicates the results of regression analysis assuming dominance of the C allele a Analysis performed on log-transformed data interaction on fasting insulin levels [5], suggesting that this genetic variant is not an important contributor to variation in fasting insulin levels in UK populations. Several reasons could explain the lack of agreement between our data and that previously published.…”

“…A common single nucleotide polymorphism (SNP) in exon 7 resulting in a leucine to valine substitution at amino acid residue 262 was genotyped in 1,031 US white individuals, a sub-group of the original population in which the quantitative trait locus was discovered [5,6]. In a dominant model, PARL genotype was associated with fasting plasma insulin levels and modified the positive association between age and fasting insulin.…”

Medical Genetics: Revenge of the thrift

“…Walder et al (2005) chose a novel tactic to identify new candidate genes in the fat sand rat. They hybridised human microarrays with reverse-transcribed skeletal muscle RNA from either lean nondiabetic or obese diabetic Psammomys.…”