Human Molecular Genetics, 2002, Vol. 11, No. 24 3019-3030
© 2002 Oxford University Press
Molecular mechanisms of autosomal recessive hypercholesterolemia
1McDermott Center for Human Growth and Development, 2Department of Molecular Genetics and 3Department of Internal Medicine, 4The Howard Hughes Medical Institute, and 5The Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA, 6The Department of Medical Therapy, University of Rome ‘La Sapienza’, Rome, Italy and 7II Department of Internal Medicine, University of Ferrara, Ferrara, Italy
Received July 11, 2002; Revised September 12, 2002; Accepted September 16, 2002
Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. 125I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs.
* To whom correspondence should be addressed at: Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9052, USA. Tel: +1 2146484774; Fax: +1 2146484837; Email: jonathan.cohen{at}utsouthwestern.edu
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