1647-P: Rare Disruptive Loss of Function Mutations in the Cluster of Differentiation 36 (CD36) Gene Overwhelmingly Cause a Metabolic Syndrome in Multiple Members of an Inbred Pedigree from One Village in Northern Israel

The metabolic syndrome consisting of type 2 diabetes (T2DM), obesity, dyslipidemia and arterial hypertension, is a complex disorder whose molecular basis is largely unknown. The cluster of differentiation 36 (CD36), a multifunctional class B scavenger receptor, has been acknowledged as a promising candidate for T2DM and its complications. More than a decade ago, a rare nonsense mutation, namely c.1079T>G (p.L360X) was identified in one Caucasian pedigree presenting with autosomal dominant diabetes (Hum mutation 2004). Recent studies however, have disputed the contribution of rare coding mutations in CD36 to T2DM and additional metabolic complications (Scientific Reports 2019). In an extended pedigree of Israeli Muslim Arab ancestry from a single village in northern Israel multiple members (n=33) with T2DM, obesity, dyslipidemia and arterial hypertension were investigated. Three affected individuals from three nuclear inbred families, originating from an extended Arab Muslim clan, underwent whole-exome sequencing that displayed several disruptive rare mutations in CD36 namely c.1011_1014delins26; p.(Arg337Serfs*23); c.1079T>G; p.(Leu360*); and c.1202_1205delTATT; p.(Val401Glufs*4). Sanger sequencing was thereafter employed to show that these mutations segregated in 30 additional affected individuals from the same clan. Our findings substantiate that CD36 plays a pivotal role in glucose homeostasis and lipid metabolism. Mutations in this gene prompt insulin resistance, obesity and dyslipidemia in humans. A rare nonsense mutation (p.L360X) in CD36 was previously found in a French pedigree presenting with autosomal dominant diabetes. Here we provide evidence that other than the p.L360X mutation, rare loss-of-function coding mutations in CD36 evoke impaired fatty acid metabolism, glucose intolerance, type 2 diabetes and arterial hypertension.