Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

Abstract

Deficiency of the serine proteinase inhibitor (serpin) α1-antitrypsin (α1AT) is the most common autosomal recessive genetic disorder in Northern Europe. α1AT is the physiological regulator of the proteolytic enzyme neutrophil elastase and severe deficiency states are associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) as a consequence of chronic proteolytic damage to the lungs. Among the known mutations of the α1AT gene causing severe α1AT deficiency and COPD a few alleles are also associated with liver disease. When expressed in cell cultures, all these particular alleles cause intracellular α1AT accumulation which appears to be a prerequisite for the development of hepatic injury. Liver disease is seen in only a small fraction of all patients carrying such alleles, however. The reason for this is not completely clear, but there is evidence that PI ZZ individuals 'susceptible' to liver disease carry an additional defect affecting protein degradation in the endoplasmic reticulum (ER). We characterise a newly identified defective http://www.stockton-press.co.uk/ejhg Mheerlen α1ATs are completely retained within synthesising cells, and the molecular defect of transportation in these two alleles may be similar to that in the common PI Z allele. The molecular defect in the PI Q0lisbon allele (Thr68Ile) shows similarity with the immediately neighbouring Mmineral springs mutation (Gly67Glu).

Inefficient Processing of an Olfactomedin-Deficient Myocilin Mutant: Potential Physiological Relevance to Glaucoma

“…Examples of other genetic disorders in which misfolded proteins are retained in the ER and in which the formation of protein aggregates is linked to their etiologies are numerous (42)(43)(44).…”

Inherited Chronic Obstructive Pulmonary Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles

“…In addition, many commercially available or laboratory-specific methods for ␣ 1 AT genotyping focus solely on the more prevalent S and Z alleles (16,35 ). These S/Z-genotyping assays require additional analysis (phenotyping or sequencing) when the patient with the observed genotype does not exhibit the expected serum (17,27,28 ). Given the availability of DNA-sequencing equipment in many hospitals, we therefore advocate direct sequencing of the relevant parts of the ␣ 1 AT gene for patients with suspected ␣ 1 AT deficiency.…”

Molecular characterization of the new defective Pbresciaalpha1-antitrypsin allele

“…Mutation analysis excluded the presence of S or Z α 1 AT alleles, while α 1 AT gene sequencing revealed the M würzburg α 1 AT allele (Poller, et al, 1999), in association with a novel α 1 AT allele (c.745G>C), coding for a mutant α 1 AT protein (Gly225Arg).…”