Severe α‐1 antitrypsin deficiency caused by Q0_Ourém allele: clinical features, haplotype characterization and history

Abstract

α-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 Q0(Ourém) , 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 Q0(Ourém) were evaluated for SERPINA1 levels, respiratory function values and lung parenchyma status (chest X-ray and computerized tomography scan). Q0(Ourém) haplotype background was characterized using seven microsatellites flanking SERPINA1 and Q0(Ourém) 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. SQ0(Ourém) , although having serum levels below the 11 µM threshold, did not necessarily result in signs of disease. MQ0(Ourém) were found to be a heterogeneous group, mainly composed of normal individuals. Eight Q0(Ourém) haplotypes were identified and the allele was estimated to have arisen 650 years ago. Q0(Ourém) was associated with mild to severe AATD and has a single origin, probably linked to the major Ourém settlements where the occurrence of severe AATD may not be explained by recent consanguinity.

Can we change a genetically determined future?

“…The clinical findings and pulmonary function deterioration observed in this case are in agreement with the findings observed in other patients with this specific mutation6 as well as in other patients with different null mutations described in previously published papers 7 8. Augmentation therapy provided clinical improvement, even without functional enhancement (table 1), which is also in agreement with the majority of published papers regarding this type of therapy2 (even though most of them are not null allele cases).…”

“…The finding of this novel mutation prompted further evaluation 1 6. This mutation is thought to have originated in the middle ages, in the region of Ourém, Portugal, and then geographically dispersed, being subsequently identified in other regions of mainland Portugal.…”

“…Screening of close relatives allowed the detection of four children carrying the mutation—four heterozygotes (3 MQ0 and 1 SQ0) 6. Evaluation of the other relatives showed seven individuals carrying the mutation (3 Q0 homozygous and 4 heterozygous).…”

Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal

“…To improve haplotype inference for microsatellite data we used haplotypes derived from two-generation studies of Portuguese families [18]. For estimating the ages of rare alleles we employed the method of the decay of haplotype sharing implemented in the DHSMAP software as previously described [32,33]. The analyses were run separately for each allele using as control a sample of 42 Portuguese chromosomes surveyed in this or in previous studies [18,34].…”

“…The Q0 Our em is described as a null allele resulting from a thymine duplication in the 352e353 codons of a M3 allele, leading to a frameshift and premature termination at 376 position (p.Leu353Phefs*24) [33,48]. This variant was previously identified in several families from Central Portugal and more recently, in five unrelated AATD patients living in La Palma (Canary Islands, Spain) [49].…”