NUCLEOTIDE INSERTION AND FRAMESHIFT CAUSE ANALBUMINEMIA IN AN ITALIANFAMILY

In analbuminemia, a very rare inherited syndrome, subjects produce lit tle or no albumin (1/100th to 1/1000th normal), presumably because of a mutation in the albumin gene; yet, they have only moderate edema and few related symptoms owing to a compensatory increase in other plasma proteins. Because of the virtual absence of albumin the defect must b e identified at the DNA level. In this study the mutation causing anal buminemia in an Italian family was investigated by analysis of DNA fro m a mother and her daughter. The mother was homozygous for the trait a nd had a serum albumin value of <0.01 g/dl (about 1/500th normal); the daughter was heterozygous for the trait and had a nearly normal album in value. Molecular cloning and sequence analysis of DNA from both mot her and daughter showed that the mutation is caused by a nucleotide in sertion in exon 8; this produces a frameshift leading to a premature s top, seven codons downstream. The methods of heteroduplex hybridizatio n and single-strand conformation polymorphism were used to compare the DNA of the mother and daughter to the DNA of two unrelated analbumine mic individuals (one Italian and one American). This showed that all t hree analbuminemic individuals had different mutations; these also dif fered from the mutation in the only human case previously studied at t he DNA level, which was a splicing defect affecting the ligation of th e exon 6-exon 7 sequences. Thus, analbuminemia may result from a varie ty of mutations and is genetically heterogeneous.