Three new Alpha1-Antitrypsin deficiency variants help to define a C-Terminal region regulating conformational change and polymerization

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state

Clinical manifestations in patients with PI*MMMalton genotypes. A matter still unsolved in alpha-1 antitrypsin deficiency

We report the genetic variants associated with alpha-1 antitrypsin deficiency (AATD) in 117 patients admitted to our outpatient clinic and characterized by a serum concentration of AAT lower than 113 mg/dL. We focused on the M-like heterozygous variant of the SERPINA1 gene called PI*MMMalton, and describe three patients with this variant. While the role of homozygous AATD in liver and pulmonary disease is well established, the association between heterozygous AATD and chronic liver and pulmonary disease is still under investigation. The PI*MMMalton genotype was found in 5.8% of patients with a pathological genotype of AATD and in 14.3% of the subjects when considering only those with intermediate AATD. There were no liver or renal abnormalities in patients with the PI*MMMalton genotype. The PI*MMMalton patients included here showed a normal liver function, and none had renal function abnormalities or abdominal aortic aneurysm. Only a prevalence of lung disease was detected

Alpha-1 antitrypsin deficiency in Italy: regional differences of the PIS and PIZ deficiency alleles

Background. Critical to the effective diagnosis and management of disease is information on its prevalence in a particular geographic area such as Italy. Alpha-1- antitrypsin deficiency (AAT Deficiency) is one of the most common serious hereditary diseases in the world, but its prevalence varies markedly from one country to another. AAT Deficiency affects at least 120.5 million carriers and deficient subjects worldwide for the two most prevalent deficiency alleles PIS and PIZ. This genetic disease is known to exist in Italy and is related to a high risk for development of jaundice in infants, liver disease in children and adults, and pulmonary emphysema in adults. Methods. Studies on the genetic epidemiology of AAT Deficiency has resulted in the development of a unique database that permits a unique analysis of the geographic distribution in 14 different regions located at random from Piemonte to Sicilia. Results. The use of Hardy-Weinberg statistical analysis to evaluate the distribution of these two deficiency alleles has demonstrated striking differences in the frequencies of these two deficiency alleles in these 14 different regions with 23/84 pair wise combinations significantly different (P=0.05) for PIS, and 5/84 combinations for PIZ. Conclusions. These findings demonstrate differences that impact the standards of care and diagnosis of AAT Deficiency in Italy since the prevalence of these deficiency alleles is not uniform throughout the country

Alpha1-antitrypsin deficiency - diagnostic testing and disease awareness in Germany and Italy.

Summary Background Alpha 1 -antitrypsin (AAT) deficiency, although largely under-diagnosed, is the underlying cause of approximately 1% of COPD cases. Lack of awareness leads to long delays in diagnostic testing. Subsequently, lifestyle and treatment choices with potentially positive effects on prognosis may be postponed. Methods Data on the testing and diagnostic practices for AAT deficiency were derived from the University of Pavia, Italy, and the University of Marburg, Germany. In addition, a survey of physicians was undertaken to explore their awareness and attitudes toward AAT deficiency. Results In Pavia and Marburg, 125 and 729 patients, respectively, were identified with severe AAT deficiency between July 2006 and June 2011. The median time interval between the onset of symptoms and diagnosis was 6 years (interquartile range [IQR], 11; range, 0–40) and 7 years (IQR, 13; range, 0–73), respectively. Augmentation therapy was initiated almost immediately in Germany while treatment was delayed by 3 months in Italy (IQR, 5.25; range, 1–118). Survey data (Italy, n = 181; Germany, n = 180) revealed that pulmonologists had greater knowledge of AAT deficiency than internists and general practitioners, however, overall, only 18–25% of physicians tested all COPD patients. One-third of the respondents stated that they "sometimes" offered augmentation therapy to patients diagnosed with AAT deficiency. Conclusions Major obstacles to AAT deficiency testing are physicians' attitudes and lack of understanding of the condition. A greater adherence to the guidelines that recommend diagnostic testing of all COPD patients, coupled with simpler testing protocols, may decrease delays and positively impact patient outcomes

The dust envelope of the pre-planetary nebula IRAS19475+3119

We present the spectral energy distribution (SED) of the pre-planetary nebula, IRAS 19475+3119 (I19475), from the optical to the far-infrared. We identify emission features due to crystalline silicates in the ISO SWS spectra of the star. We have fitted the SED of I19475 using a 1-D radiative transfer code, and find that a shell with inner and outer radii of 8.8X10^{16} and 4.4X10^{17}cm, and dust temperatures ranging from about 94K to 46K provide the best fit. The mass of this shell is greater than/equal to 1[34cm^{2}g^{-1}/kappa(100micron)][delta/200]M_Sun, where kappa(100micron) is the 100micron dust mass absorption coefficient (per unit dust mass), and delta is the gas-to-dust ratio. In agreement with results from optical imaging and millimeter-wave observations of CO emission of I19475, our model fits support an r^{-3} density law for its dust shell, with important implications for the interaction process between the fast collimated post-AGB winds and the dense AGB envelopes which results in the observed shapes of PPNs and PNs. We find that the observed JCMT flux at sub-millimeter wavelengths (850micron) is a factor ~ 2 larger than our model flux, suggesting the presence of large dust grains in the dust shell of I19475 which are not accounted for by our adopted standard MRN grain size distribution.Comment: 38 pages, 8 figures. Accepted for publication in Ap

Dust formation around AGB and SAGB stars: a trend with metallicity?

We calculate the dust formed around AGB and SAGB stars of metallicity Z=0.008 by following the evolution of models with masses in the range 1M<M<8M throughthe thermal pulses phase, and assuming that dust forms via condensation of molecules within a wind expanding isotropically from the stellar surface. We find that, because of the strong Hot Bottom Burning (HBB) experienced, high mass models produce silicates, whereas lower mass objects are predicted to be surrounded by carbonaceous grains; the transition between the two regimes occurs at a threshold mass of 3.5M. These fndings are consistent with the results presented in a previous investigation, for Z=0.001. However, in the present higher metallicity case, the production of silicates in the more massive stars continues for the whole AGB phase, because the HBB experienced is softer at Z=0.008 than at Z=0.001, thus the oxygen in the envelope, essential for the formation of water molecules, is never consumed completely. The total amount of dust formed for a given mass experiencing HBB increases with metallicity, because of the higher abundance of silicon, and the softer HBB, both factors favouring a higher rate of silicates production. This behaviour is not found in low mass stars,because the carbon enrichment of the stellar surface layers, due to repeated Third Drege Up episodes, is almost independent of the metallicity. Regarding cosmic dust enrichment by intermediate mass stars, we find that the cosmic yield at Z=0.008 is a factor 5 larger than at Z=0.001. In the lower metallicity case carbon dust dominates after about 300 Myr, but at Z=0.008 the dust mass is dominated by silicates at all times,with a prompt enrichment occurring after about 40 Myr, associated with the evolution of stars with masses M =7.5 -8M.Comment: 14 pages, 10 figures, 2 Tables, accepted for publication in MNRA