Thromb Haemost 2012; 107(04): 673-680
DOI: 10.1160/TH11-09-0671
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Molecular analysis and genotype-phenotype correlation in patients with antithrombin deficiency from Southern Italy

Giuseppe Castaldo
1   CEINGE-Biotecnologie Avanzate, Naples, Italy
2   Dipartimento di Biochimica e Biotecnologie Mediche, Naples, Italy
,
Anna Maria Cerbone
3   Centro di Riferimento Regionale per le Emocoagulopatie, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli “Federico II”, Naples, Italy
,
Anna Guida
3   Centro di Riferimento Regionale per le Emocoagulopatie, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli “Federico II”, Naples, Italy
,
Igor Tandurella
1   CEINGE-Biotecnologie Avanzate, Naples, Italy
2   Dipartimento di Biochimica e Biotecnologie Mediche, Naples, Italy
,
Rosaria Ingino
1   CEINGE-Biotecnologie Avanzate, Naples, Italy
2   Dipartimento di Biochimica e Biotecnologie Mediche, Naples, Italy
,
Antonella Tufano
3   Centro di Riferimento Regionale per le Emocoagulopatie, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli “Federico II”, Naples, Italy
,
Carlo Ceglia
1   CEINGE-Biotecnologie Avanzate, Naples, Italy
2   Dipartimento di Biochimica e Biotecnologie Mediche, Naples, Italy
,
Matteo Nicola Dario Di Minno
3   Centro di Riferimento Regionale per le Emocoagulopatie, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli “Federico II”, Naples, Italy
,
Anna Lilia Ruocco
3   Centro di Riferimento Regionale per le Emocoagulopatie, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli “Federico II”, Naples, Italy
,
Giovanni Di Minno
3   Centro di Riferimento Regionale per le Emocoagulopatie, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli “Federico II”, Naples, Italy
› Author Affiliations
Financial support: This study has been supported by: i) a grant from Ministero dell’Istruzione, dell’ Università e della Ricerca, PRIN 2008: “Farmacogenetica degli antiaggreganti: identificazione di varianti geniche comuni quali alleli di suscettibilità per una farma-coterapia su base individuale”; ii) a grant from Regione Campania (DGRC 1901/09).
Further Information

Publication History

Received: 27 September 2011

Accepted after major revision: 27 March 2011

Publication Date:
29 November 2017 (online)

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Summary

We sequenced the SERPINC1 gene in 26 patients (11 males) with antithrombin (AT) deficiency (22 type I, 4 type II), belonging to 18 unrelated families from Southern Italy. Heterozygous mutations were identified in 15/18 (83.3%) families. Of them, eight were novel mutations, each being identified in one family. Seven clearly cause impaired protein synthesis (four frameshift, one non-stop, one splicing and one 21bp deletion). One, present in a single patient, is a missense mutation thought to be causative because: a) it is absent in 100 chromosomes from controls; b) it involves a highly conserved amino acid, whose change is predicted to impair AT activity; c) no other mutation is present in the propositus. Severe mutations (i.e. nonsense, frameshift, deletions) were invariably identified in type I patients. In type II patients, 3/4 were missense mutations; the fourth leads to a 19 nucleotides shift in the stop codon. In addition to the type of mutation, the co-existence of other predisposing factors in most patients helps explain the severity of the present type I cases (age at first event, recurrence during prophylaxis). In the five families in which there was more than one member affected, the same genotype and a concordant clinical expression of the disease were found. We conclude that the molecular bases of AT deficiency in Southern Italy are different as compared to other geographic areas, and that molecular analysis and the study of the effect of the mutation may help predict the clinical expression of the disease.