Skip to content

Advertisement

  • Letter to the Editor
  • Open Access

Description of 22 new alpha-1 antitrypsin genetic variants

  • 1, 2,
  • 3, 4Email authorView ORCID ID profile,
  • 3,
  • 1,
  • 1,
  • 5,
  • 3, 6,
  • 3,
  • 5,
  • 3, 7 and
  • 1, 2
Contributed equally
Orphanet Journal of Rare Diseases201813:161

https://doi.org/10.1186/s13023-018-0897-0

  • Received: 26 April 2018
  • Accepted: 23 August 2018
  • Published:

Abstract

Alpha-1 antitrypsin deficiency is an autosomal co-dominant disorder caused by mutations of the highly polymorphic SERPINA1 gene. This genetic disorder still remains largely under-recognized and can be associated with lung and/or liver injury. The laboratory testing for this deficiency typically comprises serum alpha-1 antitrypsin quantification, phenotyping according to the isoelectric focusing pattern and genotyping if necessary. To date, more than 100 SERPINA1 variants have been described and new genetic variants are frequently discovered. Over the past 10 years, 22 new genetic variants of the SERPINA1 gene were identified in the daily practice of the University Medical laboratories of Lille and Lyon (France). Among these 22 variants, seven were Null alleles and one with a M1 migration pattern (M1Cremeaux) was considered as deficient according to the clinical and biological data and to the American College of Medical Genetics and Genomics (ACMG) criteria. Three other variants were classified as likely pathogenic, three as variants of uncertain significance while the remaining ones were assumed to be neutral. Moreover, we also identified in this study two recently described SERPINA1 deficient variants: Trento (p.Glu99Val) and SDonosti (p.Ser38Phe). The current data, together with a recent published meta-analysis, represent the most up-to-date list of SERPINA1 variants available so far.

Keywords

  • Alpha-1 antitrypsin deficiency
  • SERPINA1 genotyping
  • Null alleles

Alpha-1 antitrypsin (A1AT) is the main circulating protease inhibitor, protecting the lung parenchyma against proteolytic attacks. Alpha-1 antitrypsin deficiency (AATD) is a common but still largely under-recognized genetic disorder. It predisposes to liver and lung diseases and rarely to granulomatosis with polyangiitis and necrotizing panniculitis [1]. The wild-type allele is called PI*M while the most common deficient alleles are known as PI*S and PI*Z, according to their isoelectrofocusing (IEF) pattern. AATD-associated liver disease, observed for the deficient variants Z, SIiyama and MMalton, can be attributed to intracellular polymerization of the misfolded protein leading to endoplasmic reticulum storage disease. Mild liver storage is observed with the S variant which is probably degraded before secretion [2].

The medical indications for AATD screening were either a pulmonary or hepatic disorder or when a routine protein electrophoresis fortuitously revealed a splitting (with or without decrease) of the α1-globulin fraction at protein electrophoresis. The biochemistry laboratories of the academic medical centers of Lyon and Lille (France) currently investigate AATD by serum immunochemical quantification and IEF of A1AT. In the laboratory of Lyon, IEF is carried out on polyacrylamide gels based on the method previously described [3] with slight modifications of pH gradient (4.2–4.9). In the laboratory of Lille, IEF is performed on agarose gels using commercially available kits and immuno-enzymatic revelation (Sebia, Evry, France) [4]. In both laboratories, A1AT inhibitory activity may also be assessed through the serum elastase inhibitory capacity (SEIC) which relies on the inhibition measurement of the hydrolytic activity of the porcine pancreatic elastase by A1AT on a chromogenic substrate (N-Succinyl-Ala-Ala-Ala-p-nitroanilide). This kinetic spectrophotometric test, adapted from the method previously described by Klumpp and Bieth [5], was developed in close collaboration by the two laboratories so that the results could be comparable [6]. Using the correlation between A1AT concentration and SEIC, a theoretical SEIC can be calculated and compared to the measured SEIC with R being the ratio between the measured SEIC and the expected SEIC. For patients in heterozygosity with a new variant, R below 0.8 is presumptive of a dysfunctional variant.

This combination of techniques is sufficient to characterize up to 95% of A1AT abnormalities, mainly ZZ, SZ and SS phenotypes [1, 6, 7]. For the other cases (i.e. unexplained low A1AT level, unusual IEF pattern or IEF pattern inconsistent with clinical history), Sanger sequencing of the SERPINA1 gene including coding exons, 5′ and 3′ untranslated regions (UTRs) and splice boundaries is performed and can be extended to intronic sequences by Next Generation Sequencing technology [8]. All sequence variations are named according to the Human Genome Variation Society (HGVS) and using the reference transcript NM_000295.4 which includes the 24 residues of the signal peptide.

Over the past 10 years, more than 1200 A1AT genotyping analyses performed in our two centers led to the identification of 22 new variants in 35 patients aged from 7 to 81 years (Table 1 and Fig. 1). It is noteworthy that 4 of them were already cited but neither named nor phenotypically or clinically described [9]. According to their IEF pattern and the birth place of the probands, we named them SRoubaix, WSaint-Avre, M1Lille and M1Lyon. The criteria of the American College of Medical Genetics and Genomics (ACMG) were used to classify these 22 variants as benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic [10]. Since we did not have the possibility to test them in expression vectors like HEK293T/17 or Hepa1–6 cells, the available clinical and biochemical data of A1AT were considered, as well as the results of two in silico pathogenicity predictors, shown to have a sensitivity of 0.75 for SERPINA1 mutations [11]. The first one, namely SIFT for Sorting Intolerant From Tolerant, ranges from 0.00 to 1 and is mainly based on amino-acid conservation scores. A SIFT score between 0 and 0.05 is highly predicting of an affected protein function. The second one, namely PolyPhen-2 HVAR, proposes a prediction confidence score between 0.00 and 1.00 which uses multiple alignment and protein structural data. A PolyPhen-2 score higher than 0.8 is considered as probably damaging. The recently described REVEL (for Rare Exome Variant Ensemble Learner) method [12] was also used since it had been shown to be the most suitable one for the prediction of pathogenic A1AT variants [11]. Briefly, a REVEL score of less than 0.354 is highly predictive of a benign character of the variant whereas a score of more than 0.618 is highly predictive of pathogenicity.
Table 1

Molecular, biological and clinical characteristics of the 22 new SERPINA1 variants

Variant name

NM_000295.4 (24 amino-acids signal peptide included)

Genetic back-ground

Clinical data

Biological data

ACMG scorec

dbSNP or Clinvar ID

Exon (II-V)

c.DNA

AA change

Sex

Age (years)

Circumstance of discovery

Pulmonary/hepatic status

AATa (g/L)

SEICa (IEU/L)

Rb

IEF (PI)

CRP (mg/L)

Genotype

GSaint-sorlin

/

Exon V

1252A > T

Lys418*

M2

34

IgA nephropathy

No

2.06

37,164

1.28

GM3

19

GSaint-sorlin M3

3

M1Brest

rs774775536

Exon IV

962A > G

Tyr321Cys

M1

19

Familial screening

No

0.66

11,020

1.07

MZ

na

M1Brest Z

2

M1Bruxelles

/

Exon II

116A > T

His39Leu

M1

49

Elevated plasma GGT

Cholestasis

0.83

12,423

1.00

Heterogeneous pattern

na

M1Bruxelles ZAugsburg

2

M1Cremeaux

/

Exon V

1074 T > A

His358Gln

M1

39

Abnormal serum protein electrophoretic pattern

No

0.23

na

na

na

na

M1Cremeaux Z

5

19

Familial screening

No

1.01

na

na

na

na

M1Cremeaux M1

37

Familial screening

No

0.88

11,120

0.83

na

na

M1Cremeaux M2

15

Familial screening

No

na

na

na

na

na

M1Cremeaux M1

M1Lille

rs141095970

Exon III

879C > A

His293Gln

M1

33

Hepatic cytolysis Cholestasis, SLE

Cirrhosis

1.45

21,625

1.06

M

<  3

M1Lille M1

2

M1Lyon

rs141620200

Exon IV

922G > T

Ala308Ser

M1

10

Cystic fibrosis

Liver transplant

1.66

na

na

na

na

M1Lyon Z

2

40

Familial screening

No

1.15

16,165

0.96

M1S

na

M1Lyon S

7

Familial screening

No

1.14

14,172

0.85

M1 M2

na

M1Lyon M2

15

Immune deficiency

No

1.38

19,240

0.99

M

na

M1Lyon M1

79

na

Emphysema

2.35

32,937

1.03

M

na

M1Lyon M1

79

na

Bronchiectasis

2.20

28,510

0.95

M

na

M1Lyon M1

36

Fertility tests

No

0.70

9556

0.88

MZ

na

M1Lyon Z

46

Familial screening

No

0.82

11,190

0.90

MZ

na

M1Lyon Z

MRouen

rs764726147

Exon II

188G > A

Arg63His

M1/M2

45

Familial screening

No

na

na

na

na

na

MRouen M1 or MRouen M2

3

M1Saint-rambert

/

Exon II

356G > T

Gly119Val

M1

73

Solitary bone plasmocytoma

No

1.63

21,879

0.94

M1

17

M1Saint-rambert M1

2

M1

37

na

No

na

na

na

ni

na

M1Saint-rambert M2

OThonon-les-bains

rs759578830

Exon II

547G > A

Asp183Asn

M1

43

Irritable Bowel syndrome

No

1.30

15,521

0.82

M2O

5

M2 OThonon-les-bains

2

PLoyettes

rs766260108

Exon III

734 T > C

Met245Thr

M1

71

CLL and type 2 diabetes

No

1.26

11,347

0.62

PS

23

PLoyettes S

4

PSolaize

RCV000206568.1

Exon III

735G > A

Met245Ile

M2

18

Crohn’s disease

No

1.26

14,318

0.79

M3Pfast

d

M3 PSolaize

4

SRoubaix

rs11575873

Exon II

211A > C

Ser71Arg

M1

69

Cholestasis

HCV Cirrhosis

1.29

18,314

1.00

MS

60

M2 SRoubaix

2

WSaint-Avre

rs537285845

Exon II

436G > A

Glu146Lys

M1

34

Abnormal serum protein electrophoretic pattern

No

0.82

9871

0.80

ni

na

WSaint-Avre Z

3

M1

8

Biliary atresia

Pre-liver transplant data, probably on inflammatory status

1.47

na

na

M1W

na

M1 WSaint-Avre

WVernaison

/

Exon II

449 T > G

Leu150Arg

M1

80

MALT lymphoma

Sjogren’s syndrome

Systemic necrotizing vasculitis

No

1.10

12,376

0.79

SW

35

S WVernaison

4

XCuris

rs755851961

Exon III

811A > G

Asn271Asp

M1

21

Cystic fibrosis

No

1.34

24,121

1.24

M2X

2

M2 XCuris

2

Q0Achicourt

rs750779440

Intron 3

917 + 1G > A

/

S

59

Dyspnea

Emphysema

< 0.10

2045

ns

No band

<  3

Q0Achicourt Q0Clayton

5

Q0Amiens

rs781591420

Intron 4

1065 + 1G > A

/

M1

81

Abnormal serum protein electrophoretic pattern

No

1.18

17,419

1.03

M

na

M1 Q0Amiens

5

35

Neutropenia

No

0.76

11,741

1.01

M

<  3

M3 Q0Amiens

Q0Casablanca

RCV000408906.1

Exon II

288_291del

His97Metfs*7

M2

21

Neutropenia

Bronchiectasis

< 0.10

3747

ns

No band

15

Q0Casablanca homozygous

5

Q0Lille

Z

36

Pneumothorax

Recurrent pneumothorax

1.40

19,317

0.98

M

231

M1 Q0Lille

5

Q0Montluel

rs760849035

Exon V

1237_1239del

Val413*

M1

51

Thrombophilia screening

No

0.66

7547

0.72

M1

5

M1 Q0Montluel

5

Q0Saint-Avold

/

Intron 3

918 – 1G > A

/

M1

63

na

Emphysema

0.21

5898

1.30

Z

na

Q0Saint-Avold Z

5

Q0Saint-Etienne

/

Exon II

559A > T

Lys187*

M4

25

AATD familial screening

No

0.74

6647

0.58

M3

na

M3 Q0Saint-Etienne

5

CRP: C-Reactive Protein

na not available, ni not interpretable (unusual IEF pattern), ns not significant, CLL chronic lymphocytic leukemia, GGT gamma-glutamyl transpeptidase, HCV hepatitis C virus, MALT mucosa-associated lymphoid tissue, SLE Systemic lupus erythematosus

a Normal ranges in serum: A1AT: 0.90–2.00 g/L; SEIC (serum elastase inhibitory capacity): 17,500–31,500 IU/L.

b R = measured SEIC / expected SEIC; expected SEIC is based on the correlation between the measured SEIC and the corresponding AAT level according to the following linear relationship established from 10,863 individuals: SEIC (IU/L) = 12,784 x A1AT (g/L) + 1855. Measured SEIC< 17,500 IEU/L and/or R < 0.8 may result from A1AT functional deficiency

c ACMG classification: 1 = benign, 2 = likely benign, 3 = uncertain significance, 4 = likely pathogenic, 5 = pathogenic

d inflammatory electrophoretic profile

*nomenclatura rule for stop codon

Fig. 1
Fig. 1

IEF patterns of some frequent and rare A1AT phenotypes (polyacrylamide gels with Coomassie blue staining). 1, 33: M1M3; 2, 15, 18: M1S; 3, 17: PLoyettes S; 4: M3PLoyettes; 5, 31: M1Z; 6, 11, 20: M1M4; 7: M3PSolaize; 8, 10, 19, 21, 24, 27, 28: M1M2; 9:M1M1 12: M2SRoubaix; 13: SWVernaison; 14: M3S; 16: M2P; 22: M2XChristchurch; 23: M1XChristchurch; 25: M2XCuris; 26: M1XChristchurch; 29, 32: GSaint-SorlinM1; 30: IM3

Seven new variants were assumed to be Null ones: Q0Lille, Q0Casablanca, Q0Saint-Etienne, Q0Achicourt, Q0Saint-Avold, Q0Amiens and Q0Montluel. They resulted from splice-site, non-sense or frame shift mutations leading to premature stop codons with biosynthesis of truncated proteins or pre-mRNA degradation by the nonsense mediated decay mechanism. Interestingly, the c.288_291del frame shift mutation gives rise to two different SERPINA1 Null variants which are associated with distinct genetic backgrounds: M2 for Q0Casablanca and Z for Q0Lille. The c.559A > T (Q0Saint-Etienne) and c.1237_1239del (Q0Montluel) mutations lead to a premature stop codon while Q0Achicourt, Q0Saint-Avold and Q0Amiens are caused by splicing abnormalities. It is noteworthy that Q0Achicourt and Q0Saint-Avold, found in young patients presenting with emphysema, were both in compound heterozygosity with another deficient SERPINA1 allele (Q0Clayton and Z, respectively).

The M1Cremeaux variant was identified in four members of a same family (two sisters and their sons). The propositus was a 36-year-old woman without any pulmonary or hepatic disorder harboring the M1Cremeaux variant in heterozygosity with the dysfunctional Z variant. A1AT biochemical analysis was prescribed because of low α1-globulin fraction at protein electrophoresis during a hair loss exploration. Despite the absence of any specific clinical impact, M1Cremeaux was considered as a deficient A1AT variant (ACMG class5) for four reasons: (i) the A1AT serum level was significantly decreased (0.23 g/L in heterozygosity with the Z allele and from 0.88 to 1.01 g/L in association with a M1 or M2 allele), (ii) the mutation was located at the beginning of the 5Aβ-strand which is an important region for the protein stability [1] (iii) the pathogenic A1AT King variant affects the same amino-acid (p.His358Asp) [13] and (iv) the SIFT score (0.48) was normal but the PolyPhen-2 and REVEL scores (0.999 and 0.650) were highly predictive of pathogenicity.

The two P variants, PLoyettes and PSolaize, were suspected to be dysfunctional according to their decreased elastase inhibitory activity demonstrated by R values of 0.62 and 0.79, respectively. Sustaining our hypothesis, REVEL, SIFT and PolyPhen-2 scores predicted PLoyettes (0.933, 0 and 1.00, respectively) and PSolaize (0.597, 0 and 0.623, respectively) as deleterious. The Wvernaison variant also harbored a decreased elastase inhibitory activity (R value 0.79) and an IEF pattern with almost undetectable bands; nevertheless, SIFT and PolyPhen-2 scores predicted it as benign (0.08 and 0.432 respectively) but not the REVEL score of 0.638. Moreover, these three variants were identified in patients with an inflammatory status (CRP plasma levels higher than 10 mg/L) that probably led to overestimation of the recorded A1AT levels. They were thus classified as likely pathogenic according to ACMG criteria (class 4).

While caused by a non-sense mutation, A1AT GSaint-Sorlin (c.1252A > T; p.Lys418*) was ranged as variant of uncertain significance (class 3) since the A1AT biochemical data were normal. As the premature stop codon is located on the very last triplet of the gene, the final protein lacks only one amino-acid and it seems to have no consequence on its synthesis or functional activity. Conversely, the M1Rouen variant was also ranged in class 3 and not considered as benign or likely benign because: (i) it appears at very low allelic frequencies in databases (ExAC and Topmed: 0.0012%), (ii) a pathogenic variant on the same amino-acid (namely, the I variant p.Arg63Cys) has been described and (iii) we could not get any serum sample to assess A1AT quantification and SEIC. In detail, the SIFT and PolyPhen-2 algorithms classify the I variant as deleterious (0 and 1, respectively) while they are contradictory for the M1Rouen variant (0.04 and 0.185, respectively). A border-line R ratio of 0.8 was obtained for an asymptomatic 34 -year -old woman harboring the WSaint -Avre variant in heterozygosity with the dysfunctional Z variant. According to its low frequency in databases (ExAC: 0.0032%) and to its SIFT and PolyPhen-2 scores (1 and 0.000 respectively), WSaint -Avre was also ranged in class 3 of ACMG classification.

The remaining eight variants were classified as likely benign (class 2) because in silico algorithms predicted no impact on gene product and the A1AT quantitation and SEIC measures revealed no abnormality.

Very interestingly, we also identified during the course of this study two SERPINA1 deficient variants that were very recently described: Trento (p.Glu99Val) [14] and SDonosti (p.Ser38Phe) [15]. The Trento variant showed compromised conformational stability after secretion from the hepatocyte [14]. In our cohort, this variant was present in heterozygosity with the MMalton variant in a 42-year-old man with a low A1AT level (0.85 g/L) presenting with hepatic fibrosis. The SDonosti variant was shown to form intra-cellular polymers that prevent its secretion from the hepatocytes. We identified the SDonosti variant in two unrelated individuals (in heterozygosity with the M1 variant and with the S variant, respectively): (i) a 64-year-old woman suffering from emphysema (A1AT level = 1.21 g/L but inflammatory status not known) and (ii) a 41-year-old man suffering from hemochromatosis (A1AT level = 0.80 g/L).

In conclusion, this study highlights the importance of the whole SERPINA1 gene sequencing (and not only the specific research of the Z and S variants) to explain some AATD clinical and biological pictures. Among these 22 new A1AT variants, a significant percentage of severely deficient ones (class 5) was observed (36.4%): Seven Q0 alleles and one deficient M1 allele (M1Cremeaux). Three variants (PLoyettes, PSolaize and WVernaison) could be classified as dysfunctional variants (class 4) mainly because of their reduced elastase inhibitory activity. Three variants (M1Rouen, GSaint -Sorlin and WSaint -Avre) were classified as variants of uncertain significance (Class 3) and the eight remaining ones as likely benign (Class 2). To note, we fortuitously observed that the IEF pattern of the SRoubaix variant depended on the migration medium: W-like on polyacrylamide gels (Lyon) and S-like on agarose gels (Lille) (Additional file 1: Figure S1). Since all patients carrying the SRoubaix variant were of North African origin, we highly speculate that this variant might correspond to the ‘old’ W3Constantine described in 1977 by Khitri [16]. The recent meta-analysis by Silva et al., completed by the present data, represents the most up-to-date list of SERPINA1 variants available so far.

Notes

Abbreviations

A1AT: 

Alpha-1-antitrypsin

AATD: 

Alpha-1-antitrypsin deficiency

IEF: 

Isoelectric focusing

SEIC: 

Serum elastase inhibitory capacity

Declarations

Acknowledgements

We thank the technical teams of the laboratories of Lyon and Lille for their skillful assistance. We are also very grateful to all the patients and their medical doctors.

Funding

This work was funded by the ‘Hospices Civils de Lyon (HCL)’ and by the ‘Centre Hospitalier Régional Universitaire (CHRU) de Lille’.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article and its additional files.

Authors’ contributions

Biochemical and genetic analysis: CR, MFO, NP, FZ, CCC, MB, PJ. Made substantial contribution to acquisition of data, analysis and interpretation of data: CR, MFO, CL, GT, JT, NA, NP, FZ, CCC, MB, PJ. Drafting manuscript: CR, MFO, FZ, CCC, MB, PJ. Revising and approving content: CR, MFO, FZ, CCC, MB, PJ. Given final approval: CR, MFO, CL, GT, JT, NA, NP, FZ, CCC, MB, PJ.

Ethics approval and consent to participate

Written informed consents were obtained from all patients for the genetic analyses.

Consent for publication

Consents for research use of the data are included in the informed consent signed by the patients.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Laboratoire de Biochimie et Biologie moléculaire Grand Est, UF “Biochimie des pathologies érythrocytaires”, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France
(2)
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team “Vascular Biology and Red Blood Cell”, Université Claude Bernard Lyon 1, Villeurbanne, France
(3)
Service de Biochimie et Biologie moléculaire “Hormonologie, Métabolisme-Nutrition, Oncologie”, CHU Lille, F-59000 Lille, France
(4)
Faculty of Pharmaceutical and Biological Sciences, UMR995, LIRIC (Lille Inflammation Research International Center), University of Lille, F-59000 Lille, France
(5)
Laboratoire d’Immunologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon & Université Claude Bernard-Lyon 1, Lyon, France
(6)
EA4483, IMPECS, Institut Pasteur de Lille, University of Lille, F-59000 Lille, France
(7)
Faculty of Pharmaceutical and Biological Sciences, EA7364, RADEME (Research team on rare developmental and metabolic diseases), University of Lille, F-59000 Lille, France

References

  1. Greene CM, Marciniak SJ, Teckman J, Ferrarotti I, Brantly ML, Lomas DA, Stoller JK, NG ME. Alpha1-antitrypsin deficiency. Nat Rev Dis Primers. 2016;2:16051. https://doi.org/10.1038/nrdp.2016.51.View ArticlePubMedGoogle Scholar
  2. Callea F, Giovannoni I, Francalanci P, Boldrini R, Faa G, Medicina D, Nobili V, Desmet VJ, Ishak K, Seyama K, Bellacchio E. Mineralization of alpha-1-antitrypsin inclusion bodies in Mmalton alpha-1-antitrypsin deficiency. Orphanet J Rare Dis. 2018;13 https://doi.org/10.1186/s13023-018-0821-7.
  3. Arnaud P, Chapuis-Cellier C. Alpha 1-antitrypsin. Methods Enzymol. 1988;163:400–18.View ArticleGoogle Scholar
  4. Zerimech F, Hennache G, Bellon F, Barouh G, Jacques Lafitte J, Porchet N, Balduyck M. Evaluation of a new Sebia isoelectrofocusing kit for alpha 1-antitrypsin phenotyping with the Hydrasys system. Clin Chem Lab Med. 2008;46(2):260–3. https://doi.org/10.1515/CCLM.2008.036.View ArticlePubMedGoogle Scholar
  5. Klumpp T, Bieth JG. Automated measurement of the elastase-inhibitory capacity of plasma with a centrifugal analyzer. Clin Chem. 1979;25(6):969–72.PubMedGoogle Scholar
  6. Balduyck M, Odou MF, Zerimech F, Porchet N, Lafitte JJ, Maitre B. Diagnosis of alpha-1 antitrypsin deficiency: modalities, indications and diagnosis strategy. Rev Mal Respir. 2014;31(8):729–45. https://doi.org/10.1016/j.rmr.2014.06.001.View ArticlePubMedGoogle Scholar
  7. Stockley RA, Luisetti M, Miravitlles M, Piitulainen E, Fernandez P. Alpha one international registry group: ongoing research in Europe: alpha one international registry (AIR) objectives and development. Eur Respir J. 2007;29(3):582–6. https://doi.org/10.1183/09031936.00053606.View ArticleGoogle Scholar
  8. Joly P, Francina A, Lacan P, Heraut J, Chapuis-Cellier C. Place of genotyping in addition to the phenotype and the assay of serum alpha-1 antitrypsin. Ann Biol Clin. 2011;69(5):571–6. https://doi.org/10.1684/abc.2011.0613.View ArticleGoogle Scholar
  9. Silva D, Oliveira MJ, Guimaraes M, Lima R, Gomes S, Seixas S. Alpha-1-antitrypsin (SERPINA1) mutation spectrum: three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. Respir Med. 2016;116:8–18. https://doi.org/10.1016/j.rmed.2016.05.002.View ArticlePubMedGoogle Scholar
  10. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Giacopuzzi E, Laffranchi M, Berardelli R, Ravasio V, Ferrarotti I, Gooptu B, Borsani G, Fra A. Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency. Hum Mutat. 2018; https://doi.org/10.1002/humu.23562.View ArticleGoogle Scholar
  12. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, Musolf A, Li Q, Holzinger E, Karyadi D, Cannon-Albright LA, Teerlink CC, Stanford JL, Isaacs WB, Xu J, Cooney KA, Lange EM, Schleutker J, Carpten JD, Powell IJ, Cussenot O, Cancel-Tassin G, Giles GG, MacInnis RJ, Maier C, Hsieh CL, Wiklund F, Catalona WJ, Foulkes WD, Mandal D, Eeles RA, Kote-Jarai Z, Bustamante CD, Schaid DJ, Hastie T, Ostrander EA, Bailey-Wilson JE, Radivojac P, Thibodeau SN, Whittemore AS, Sieh W. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99(4):877–85. https://doi.org/10.1016/j.ajhg.2016.08.016.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Miranda E, Perez J, Ekeowa UI, Hadzic N, Kalsheker N, Gooptu B, Portmann B, Belorgey D, Hill M, Chambers S, Teckman J, Alexander GJ, Marciniak SJ, Lomas DA. A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency. Hepatology. 2010;52(3):1078–88. https://doi.org/10.1002/hep.23760.View ArticlePubMedGoogle Scholar
  14. Miranda E, Ferrarotti I, Berardelli R, Laffranchi M, Cerea M, Gangemi F, Haq I, Ottaviani S, Lomas DA, Irving JA, Fra A. The pathological Trento variant of alpha-1-antitrypsin (E75V) shows nonclassical behaviour during polymerization. FEBS J. 2017;284(13):2110–26. https://doi.org/10.1111/febs.14111.View ArticlePubMedPubMed CentralGoogle Scholar
  15. Matamala N, Lara B, Gomez-Mariano G, Martinez S, Retana D, Fernandez T, Silvestre RA, Belmonte I, Rodriguez-Frias F, Vilar M, Saez R, Iturbe I, Castillo S, Molina-Molina M, Texido A, Tirado-Conde G, Lopez-Campos JL, Posada M, Blanco I, Janciauskiene S, Martinez-Delgado B. Characterization of novel missense variants of SERPINA1 gene causing Alpha-1 antitrypsin deficiency. Am J Respir Cell Mol Biol. 2017 https://doi.org/10.1165/rcmb.2017-0179OC.View ArticleGoogle Scholar
  16. Khitri A, Benlatrache K, Martin JP. Pi W3 Constantine, new allele of Pi system. Sem Hop. 1977;53(16):909–10.PubMedGoogle Scholar

Copyright

© The Author(s). 2018

Advertisement