Abetalipoproteinemia (ABL) is an extremely rare autosomal recessive disorder, which is characterized by defective assembly and secretion of plasma apolipoprotein (apo) B-containing lipoproteins. ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTP). We sequenced the MTP gene in six Canadian subjects with ABL, of whom four were found to be simple homozygotes and two were found to be compound heterozygotes for MTP gene mutations. Of the 8 MTP gene mutations identified, 6 had not been previously reported, including two new nonsense mutations (K448X and K842X), two new missense mutations (S590I and G746E), one new frameshift mutation (1820del1) and one new splice donor site mutation (G1770A). Despite appropriate treatment with high doses of fat-soluble vitamins in all subjects, there was a wide variation in the progression and severity of the clinical phenotypes. For example, the presence of severe retinopathy and neuropathy did not correlate with the type and position of the mutation, but rather with the age at diagnosis and onset of treatment with fat-soluble vitamins. These findings suggest that genetic and non-genetic factors can modulate the clinical impact of mutant MTP in ABL patients.
Copyright 2000 Wiley-Liss, Inc.