Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategy

Abstract

A low level of high density lipoprotein (HDL) cholesterol is a strong predictor of ischaemic heart disease (IHD) and myocardial infarction. One cause of low HDL-cholesterol is Tangier disease (TD), an autosomal codominant inherited condition first described in 1961 in two siblings on Tangier Island in the United States of America. Apart from low HDL-cholesterol levels and an increased incidence of atherosclerosis, TD is characterized by reduced total cholesterol, raised triglycerides, peripheral neuropathy and accumulation of cholesteryl esters in macrophages, which causes enlargement of the liver, spleen and tonsils. In contrast to two other monogenic HDL deficiencies in which defects in the plasma proteins apoA-I and LCAT interfere primarily with the formation of HDL (refs 7-10), TD shows a defect in cell signalling and the mobilization of cellular lipids. The genetic defect in TD is unknown, and identification of the Tangier gene will contribute to the understanding of this intracellular pathway and of HDL metabolism and its link with IHD. We report here the localization of the genetic defect in TD to chromosome 9q31, using a genome-wide graphical linkage exclusion strategy in one pedigree, complemented by classical lod score calculations at this region in a total of three pedigrees (combined lod 10.05 at D9S1784). We also provide evidence that TD may be due to a loss-of-function defect.

The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway

“…Complementary sources of data were used to evaluate the genes underexpressed in the Tangier cells. In 1998, a genetic linkage strategy was used to assign the TD gene to an approximately 7-cM region of human chromosome 9q31 (21). Public database inspection revealed few named genes in this region.…”

Genetic causes of high and low serum HDL-cholesterol

“…However, it can only provide an initial localization of susceptibility genes and requires subsequent extensive fi ne-mapping studies. This approach has been successful in localizing the causative genes in rare monogenic disorders, such as Tangier disease ( 86 ), but it has been less benefi cial for common (i.e., complex) polygenic conditions. A large number of genome-wide linkage screens for continuous and dichotomous HDL-C and related traits (such as apoAI and apoAII levels) have been performed in FHA as well as nonascertained family samples from different populations [reviewed by (87)(88)(89)(90)].…”

Human ATP-binding cassette transporter 1 (ABC1): Genomic organization and identification of the genetic defect in the original Tangier disease kindred

“…Initial studies to elucidate the genetic defect in Tangier disease, using positional cloning, mapped the defective gene to a region on chromosome 9 (17). In a recent report, we (18) and others (48,49) have identified that mutations in the ABC1 gene are the molecular defect in Tangier disease.…”