Severe [alpha]-1 antitrypsin deficiency caused by Q0Ourem allele: clinical features, haplotype characterization and history

[alpha]-1 Antitrypsin deficiency (AATD) caused by null alleles is associated with the total lack of protein and generally it translates into more severe clinical features of pulmonary disease. This is the case of Q0Ourem, a rare variant found in several families of Central Portugal caused by the L353fsX376 mutation. A total of 41 patients carrying at least one copy of Q0Ourem were evaluated for SERPINA1 levels, respiratory function values and lung parenchyma status (chest X-ray and computerized tomography scan). Q0Ourem haplotype background was characterized using seven microsatellites flanking SERPINA1 and Q0Ourem age was estimated by a statistical method relying on the decay of haplotype sharing at linked markers (DHSMAP). Homozygous patients showed a compromised lung function and extensive emphysema. SQ0Ourem, although having serum levels below the 11 µM threshold, did not necessarily result in signs of disease. MQ0Ourem were found to be a heterogeneous group, mainly composed of normal individuals. Eight Q0Ourem haplotypes were identified and the allele was estimated to have arisen 650 years ago. Q0Ourem was associated with mild to severe AATD and has a single origin, probably linked to the major Ourem settlements where the occurrence of severe AATD may not be explained by recent consanguinity. [PUBLICATION ABSTRACT]