RT Journal Article
SR Electronic
T1 Identification and distribution of rare and new mutations of Alpha-1-antitrypsin in Germany
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P2037
VO 44
IS Suppl 58
A1 Christian Herr
A1 Timm Greulich
A1 Rembert Koczulla
A1 Viktor Kotke
A1 Claus Vogelmeier
A1 Robert Bals
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P2037.abstract
AB Rational: Mutations in the SERPINA-1 gene encoding the alpha-1-antitrypsin (AAT) antiprotease are a risk factor for the development of a chronic obstructive pulmonary disease (COPD). The Z- and the S-Allele are the most frequent mutations that lead to AAT-deficiency. Besides these mutations, numerous alleles have been identified, that lead to AAT-deficiency. The aim of this study was the identification of patients with rare or unknown mutations from a AAT-screening program.Methods: Individuals with a suspected AAT-deficiency were genotyped by PCR-analysis and isoelectric focusing (IEF) of serum. In individuals with low serum levels and the absence of the S or the Z allele, we performed exon sequencing of the 3 non-coding (Exon Ia-c) and 4 coding exons. To identify rare and unknown mutations, we compared the patients sequence with a reference sequence and all published rare mutations.Results: Out of 16180 analyzed individuals 98,6 % could be identified by PCR-analysis and IEF. We analyzed 1,4 % by exon sequencing and found 25 new mutations. Out of the 237 sequenced people 34% were heterozygous for PiZ plus a rare at risk mutation and 5% had a combination of PiZ and Q0. 13,5 % carried a rare base allele and neither Z or Q0 and 5,3% had a combination of PiZ and a rare base allele. Among the new mutations we found 5 potential stop mutations. The most common rare at risk mutations we found were M-Heerlen (18%) followed by M-Procida (9,5%).Conclusion: Allel-specific PCR and isoelectric focusing are proven and reliable methods to diagnose AAT-deficient patients. Genomic sequencing and subsequent genetic analysis are the most powerful additions to identifiy rare and unknown mutations.