Autosomal recessive hypercholesterolemia.

Autosomal recessive hypercholesterolemia (ARH) presents with a clinical phenotype similar to that of classical homozygous familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor gene but is more variable, generally less severe, and more responsive to lipid-lowering therapy than homozygous FH; furthermore, FH is inherited with a dominant pattern. The approximately 50 known affected ARH individuals are mostly of Sardinian or Middle Eastern origin, but rare cases of ARH have occurred worldwide. The physiological defect in ARH is a failure of some, but not all, cell types to mediate LDL receptor-dependent internalization of LDL and is caused by mutations in the gene for a putative adaptor protein called ARH.

Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment.

Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in ARH on chromosome 1p35-36, encoding a putative adaptor protein. Mutations in the gene prevent normal internalisation of the low density lipoprotein (LDL) receptor by cultured lymphocytes and monocyte-derived macrophages, but not skin fibroblasts. This newly identified disorder is characterised by severe hypercholesterolaemia, large tendon, tuberous and planar xanthomas and premature atherosclerosis.

Genetic diagnosis of familial hypercholesterolaemia: a mutation and a rare non-pathogenic amino acid variant in the same family.

Familial hypercholesterolaemia (FH), a relatively common inherited disorder, is caused by mutations in the gene for the low density lipoprotein (LDL) receptor (LDLR) that result in impaired clearance of LDL. Identification of mutations in patients with the clinical phenotype of FH allows unequivocal diagnosis in potentially affected relatives, but depends critically on distinguishing mutations that affect protein function from variants with no significant effect. A presumed functional mutation in LDLR (G198D in exon 4) was identified in two hypercholesterolaemic English brothers by high throughput screening and was not found in 550 controls.

Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia.

Objective: Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 (APOA5), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL).

Methods And Results: We performed linkage and association tests on 128 families.

Confirmed locus on chromosome 11p and candidate loci on 6q and 8p for the triglyceride and cholesterol traits of combined hyperlipidemia.

Unlabelled: Background- Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown.

Methods And Results: We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities.

Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia.

The recent characterization of a rare genetic defect causing autosomal recessive hypercholesterolemia (ARH) has provided new insights into the underlying mechanism of clathrin-mediated internalization of the LDL receptor. Mutations in ARH on chromosome 1p35-36.1 prevent normal internalization of the LDL receptor by cultured lymphocytes and monocyte-derived macrophages but not by skin fibroblasts.

Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.

Dietary fat is an important source of nutrition. Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption. The Sar1 family of proteins initiates the intracellular transport of proteins in COPII (coat protein)-coated vesicles.

Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.

Familial hypercholesterolemia is an autosomal dominant disorder with a gene-dosage effect that is usually caused by mutations in the LDL receptor gene that disrupt normal clearance of LDL. In the homozygous form, it results in a distinctive clinical phenotype, characterized by inherited hypercholesterolemia, cholesterol deposition in tendons, and severe premature coronary disease. We described previously two families with autosomal recessive hypercholesterolemia that is not due to mutations in the LDL receptor gene but is characterized by defective LDL receptor-dependent internalization and degradation of LDL by transformed lymphocytes from the patients.

A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism.

Purpose: The role of thyroxine replacement in subclinical hypothyroidism remains unclear. We performed a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of thyroxine treatment for mild subclinical hypothyroidism, defined as a serum thyroid-stimulating hormone level between 5 to 10 microU/mL with a normal serum free thyroxine level (0.8-16 ng/dL).