A nonsense mutation in the apolipoprotein C-IIPadova gene in a patient with apolipoprotein C-II deficiency.

Abstract

The apo C-II gene from a patient with apo C-1I deficiency has been sequenced after amplification by the polymerase chain reaction. A substitution of an adenosine for a guanosine at position 3002 in exon 3 of the patient's gene was identified by sequence analysis. This mutation leads to the introduction of a premature termination codon (TAA) at a position corresponding to amino acid 37 of mature apo C-II and to the formation of a new Rsa I restriction enzyme site not present in the normal apo C-II gene. Amplification of DNA from family members by the polymerase chain reaction and digestion with Rsa I established that the patient is a true homozygote for the mutation. Analysis of the patient's plasma by two-dimensional gel electrophoresis and immunoblotting detected an apo C-II that exhibited abnormal electrophoretic mobility. We propose that the C to A substitution in the apo C-Ipdova gene is the primary genetic defect that leads to premature termination and the synthesis of a truncated 36 amino acid apo C-II that is unable to activate lipoprotein lipase.

Nonsense mutation R1162X of the cystic fibrosis transmembrane conductance regulator gene does not reduce messenger RNA expression in nasal epithelial tissue.

“…Nonsense mutations have sometimes been associated with lack of mRNA and protein, as in human f3-globin (34), human a I-antitrypsin (35), and insulin receptor (36) genes, while in other cases such as that of the LDL receptor or the apolipoprotein C-II genes a stable truncated protein is synthesized (37,39). It has been suggested that mRNAs presenting translation termination mutations might be unstable since they may not be protected by ribosomes from the endogenous RNAase digestion (34).…”

Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema.

“…Normal levels of mRNA have been shown for the LDL receptor (36), for the beta-globin chain (37) and for apolipoprotein CII (38) in patients with nonsense mutations of these genes. Similar findings were reported for the dihydrofolate reductase gene in which nonsense mutations were artificially introduced at various points in the gene sequence (39).…”

Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.

“…Two additional CF patients, homozygous for the G542X nonsense mutation in exon 11, have been reported with similar clinical manifestations (12,13). Nonsense mutations in several human disease genes have been shown to cause severe reduction in mRNA levels, leading to absent protein product and severe clinical disease (14)(15)(16)(17)(18)(19)(20)(21)(22) 21 ( 11). She has very mild pulmonary disease for her age and severe pancreatic disease which have been fully described previously (1 1).…”