J. Biol. Chem., Vol. 262, Issue 25, 11999-12004, 09, 1987

alpha 1-Antitrypsin nullGranite Falls, a nonexpressing alpha 1- antitrypsin gene associated with a frameshift to stop mutation in a coding exon

T Nukiwa, H Takahashi, M Brantly, M Courtney and RG Crystal

alpha 1-Antitrypsin (alpha 1-AT) deficiency is a hereditary disorder associated with serum alpha 1-AT levels less than 35% of normal. There are two categories of alpha 1-AT genes that cause this state: the deficient alleles, in which alpha 1-AT is present in serum but in low levels, and the null alleles, in which no alpha 1-AT in serum can be attributed to the gene. The present study defines the molecular basis for the alpha 1-AT gene nullGranite Falls, identified and cloned from genomic DNA of an individual with severe alpha 1-AT deficiency and emphysema resulting from the heterozygous inheritance of the nullGranite Falls and Z alpha 1-AT genes. Sequencing of the 5'-flanking region, all five coding exons, and all exon-intron junctions of nullGranite Falls demonstrated it was identical with the common normal M1(Ala213) alpha 1-AT gene, except for two bases: a single deletion in the codon for amino acid Tyr160 of the mature protein and a single base substitution 168 base pairs 5' to exon I. Although no role for the promoter region mutation could be assigned, the coding exon deletion [Tyr(TAC)----(TA-)] resulted in a frameshift causing a stop coding to be formed approximately 44% from the N terminus of the precursor protein. Using oligonucleotide probes to evaluate the family of the index case demonstrated the deletion----frameshift/stop mutation was inherited in an autosomal co-dominant fashion. Thus, although the molecular basis for alpha 1-AT deficiency of the alpha 1-AT null haplotype such as nullGranite Falls is very different from the molecular basis of the more common deficient haplotypes such as Z, the phenotypic consequences of the two genes are similar; i.e. severe alpha 1-AT deficiency and an association of a high risk for the development of emphysema.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Prins, B. B. van der Meijden, R. J. Kraaijenhagen, and J. P.M. Wielders Inherited Chronic Obstructive Pulmonary Disease: New Selective-Sequencing Workup for {alpha}1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles Clin. Chem., January 1, 2008; 54(1): 101 - 107. [Abstract] [Full Text] [PDF]

				R. J. MASON and R. G. CRYSTAL Pulmonary Cell Biology Am. J. Respir. Crit. Care Med., April 1, 1998; 157(4): S72 - S81. [Full Text] [PDF]

				A. Ray, X. Gao, and B. K. Ray Role of a Distal Enhancer Containing a Functional NF-kappaB-binding Site in Lipopolysaccharide-induced Expression of a Novel alpha(1)-Antitrypsin Gene J. Biol. Chem., December 8, 1995; 270(49): 29201 - 29208. [Abstract] [Full Text] [PDF]