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

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

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

The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure

Clinical manifestations of a new alpha-1 antitrypsin genetic variant: Q0parma

Alpha-1 antitrypsin deficiency is an autosomal, codominant disorder caused by mutations of the SERPINA1 gene. Several mutations of SERPINA1 have been described associated with the development of pulmonary emphysema and/or chronic liver disease and cirrhosis. Here, we report a very rare PI*Q0parma variant identified for the first time in an Italian family originally from the city of Parma in Northern Italy

α1-Antitrypsin deficiency

1-Antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease. It is not a rare disorder but frequently goes underdiagnosed or misdiagnosed as asthma, chronic obstructive pulmonary disease (COPD) or cryptogenic liver disease. The most frequent disease-associated mutations include the S allele and the Z allele of SERPINA1, which lead to the accumulation of misfolded α1-antitrypsin in hepatocytes, endoplasmic reticulum stress, low circulating levels of α1-antitrypsin and liver disease. Currently, there is no cure for severe liver disease and the only management option is liver transplantation when liver failure is life-threatening. A1ATD-associated lung disease predominately occurs in adults and is caused principally by inadequate protease inhibition. Treatment of A1ATD-associated lung disease includes standard therapies that are also used for the treatment of COPD, in addition to the use of augmentation therapy (that is, infusions of human plasma-derived, purified α1-antitrypsin). New therapies that target the misfolded α1-antitrypsin or attempt to correct the underlying genetic mutation are currently under development

Metal-rich absorbers at high redshifts: abundance patterns

(Abbreviated) From six spectra of high-z QSOs, we select eleven metal-rich, Z>=Z_solar, and optically-thin to the ionizing radiation, N(HI)<10^17 cm^-2, absorption systems ranging between z=1.5 and z=2.9 and revealing lines of different ions in subsequent ionization stages. The majority of the systems (10 from 11) show abundance patterns which relate them to outflows from low and intermediate mass stars. All systems have sub-kpc linear sizes along the line-of-sight with many less than 20 pc. In several systems, silicon is deficient, presumably due to the depletion onto dust grains in the envelopes of dust-forming stars and the subsequent gas-dust separation. At any value of [C/H], nitrogen can be either deficient, [N/C]0, which supposes that the nitrogen enrichment occurs irregularly. In some cases, the lines of MgII 2796, 2803 appear to be shifted, probably as a result of an enhanced content of heavy isotopes 25Mg and 26Mg in the absorbing gas relative to the solar isotopic composition. Seven absorbers are characterized by low mean ionization parameter U, log U<-2.3, among them only one system has a redshift z>2 whereas all others are found at z ~= 1.8. Comparing the space number density of metal-rich absorbers with the comoving density of star-forming galaxies at z ~= 2, we estimate that the circumgalactic volume of each galaxy is populated by 10^7 - 10^8 such absorbers with total mass <=1/100th of the stellar galactic mass. Possible effects of high metal content on the peak values of star-forming and AGN activities at z~2 are discussed.Comment: 19 pages, 16 figures, 3 tables. Accepted for publication in A&

Carbon enrichment of the evolved stars in the Sagittarius dwarf spheroidal

We present spectra of 1142 colour-selected stars in the direction of the Sagittarius Dwarf Spheroidal (Sgr dSph) galaxy, of which 1058 were taken with VLT/FLAMES multi-object spectrograph and 84 were taken with the SAAO Radcliffe 1.9-m telescope grating spectrograph. Spectroscopic membership is confirmed (at >99% confidence) for 592 stars on the basis of their radial velocity, and spectral types are given. Very slow rotation is marginally detected around the galaxy's major axis. We identify five S stars and 23 carbon stars, of which all but four carbon stars are newly-determined and all but one (PQ Sgr) are likely Sgr dSph members. We examine the onset of carbon-richness in this metal-poor galaxy in the context of stellar models. We compare the stellar death rate (one star per 1000-1700 years) to known planetary nebula dynamical ages and find that the bulk population produce the observed (carbon-rich) planetary nebulae. We compute average lifetimes of S and carbon stars as 60-250 and 130-500 kyr, compared to a total thermal-pulsing asymptotic giant branch lifetime of 530-1330 kyr. We conclude by discussing the return of carbon-rich material to the ISM.Comment: 14 pages, 10 figures, accepted MNRA