alpha1-Antitrypsin null alleles: evidence for the recurrence of the L353fsX376 mutation and a novel G-->A transition in position +1 of intron IC affecting normal mRNA splicing.

alpha1-Antitrypsin (PI) deficiency is a common autosomal recessive disorder associated with emphysema and liver disease, which may result from a wide spectrum of mutations causing a reduction of serum levels (deficient alleles) or a total lack of circulating protein (null alleles). We report two different alleles associated with the absence of isoelectric focusing banding patterns in Portuguese patients with emphysema. The first allele, Q0(ourém), results from the recurrence of the defining mutation of the Q0(mattawa) variant (L353fsX376) on a M3 normal background. The second allele, Q0(porto), has a novel G-->A mutation at position +1 of the intron IC (IVS1C+1G-->A), which restricts mononuclear phagocyte transcripts to mRNA species resulting from the direct splice of exon IA to exon II. The absence of this normal splice alternative in the liver, where PI is primarily synthesized, provides a basis for the pathogenic effects of this mutation.