The molecular defects in lipoprotein lipase deficient patients.

The underlying molecular defects that lead to a deficiency of lipoprotein lipase in two patients from different kindreds presenting with the familial hyperchylomicronemia syndrome have been identified. Sequence analysis of amplified LPL cDNA of the patient from the Bethesda kindred revealed a single point mutation (G to A) at position 781 of the normal gene that resulted in the substitution of an alanine for a threonine at residue 176 and the loss of an SfaN1 site present in the normal LPL gene. Amplification of patient cDNA by the PCR followed by restriction enzyme digestion with SfaN1 established that the patient is a true homozygote for the defect. The proband from the second kindred was found to be a compound heterozygote for two separate allelic mutations, including a T to C transition at nucleotide 836 and a G to A mutation at base 983 that led to the substitution of Ile194 by Thr and Arg243 by His, respectively. Transient expression of the mutant LPL cDNAs from both kindreds in human embryonal kidney-293 cells resulted in the synthesis of enzymatically inactive proteins, establishing the functional significance of the mutations.