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Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia

Genes & Immunity volume 8, pages 325–333 (2007)Cite this article

Abstract

Autosomal-recessive agammaglobulinemia is a rare and heterogeneous disorder, characterized by early-onset infections, profound hypogammaglobulinemia of all immunoglobulin isotypes and absence of circulating B lymphocytes. To investigate the molecular basis of the disease, 23 patients with early-onset disease and no mutations in Bruton tyrosine kinase, the gene responsible for X-linked agammaglobulinemia, were selected and analyzed by direct sequencing of candidate genes. Two novel mutations in the μ heavy chain (μHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G>A nucleotide substitution at the −1 position of an alternative splice site in IGHM; here, we demonstrate that this mutation is indeed responsible for aberrant splicing. Comparison of bone marrow cytofluorimetric profiles in two patients carrying different mutations in the IGHM gene suggests a genotype–phenotype correlation with the stage at which B-cell development is blocked. Several new single nucleotide polymorphisms (SNPs) both in the μHC and in the λ5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology.

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Acknowledgements

We acknowledge the patients and families for their generous cooperation and the following centers participating to the AIEOP Network for Primary Immunodeficiencies: Ancona (GV Coppa, P Pierani), Bari (D DeMattia, B Martire), Bari (L Armenio, F Cardinale), Bari (F Dammacco, M Prete), Bologna (G Paolucci, M Masi, A Miniaci), Bologna Centro Operativo AIEOP (A Pession, R Rondelli), Bologna (G Ambrosioni, P Alvisi), Brescia (A Plebani, LD Notarangelo, A Soresina), Cagliari (Cao, F Cossu), Cagliari (S Del Giacco, P Manconi), Campobasso (I Evangelista), Catanzaro (S Magro, S Morgione), Catanzaro (P Strisciuglio E Anastasio), Catania (G Schillirò, A Sciotto), Chieti (R Paganelli), Como (M Sticca), Cosenza (M Candusso, L Carpino), Firenze (G Bernini, C Azzari), Genova (E Castagnola, M Gattorno), Mantova (G Pastorelli, S Fasoli), Messina (C Sampietro), Milano (MC Pietrogrande, RM Delle Piane, C Panisi) Milano (G Cambiaghi), Milano (M Pietrogrande), Milano (MG Roncarolo, A Aiuti), Monza (G Masera, A Biondi, A Sala), Napoli (C Pignata), Napoli (V Poggi, G Menna), Napoli (R Di Nardo), Napoli (A D'Apuzzo), Napoli (A Pelliccia), Napoli (A Correra), Napoli (G Marone, G Spadaro), Padova (L Zanesco, G Basso, MC Putti), Padova (G Semenzato, C Agostini), Palermo (GM Amato), Palermo (M Aricò, A Trizzino), Parma (G Izzi, P Bertolini), Pavia (F Locatelli, M Zecca), Pavia (G Rondini, GL Marseglia, R Maccario, G Bossi), Pesaro (L Felici), Pisa (P Macchia, R Consolini, C Favre), Rimini (V Vecchi, P Sacchini, G Rinaldi), Roma (AG Ugazio, P Rossi, S Livadiotti) Roma (A Stabile), Roma (M Duse), Roma (I Quinti), Roma (V Moschese), Siena (G Morgese, Acquaviva), Treviso (G De Zan), Trieste (P Tamaro, M Rabusin), Torino (PA Tovo, S Martino), Varese (L Nespoli, M Marinoni), Venezia (A Porcellini), Verona (GA Cazzola).

We thank Monica Franzoni for her helpful support in the bone marrow analysis.

This work was supported by grants from Associazione Immunodeficienze Primitive (AIP), Fondazione Golgi, and Centro Immunodeficienze M. Di Martino-Brescia to AP, and by Fondazione Telethon to SF.

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Author notes

  1. V S̆ourková

    Present address: 12Current address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Praha.,

Authors and Affiliations

  1. Medical Genetics Unit and CRBa, S.Orsola-Malpighi University Hospital, Bologna, Italy

    S Ferrari, R Zuntini, V S̆ourková & C Rossi

  2. Institute of Molecular Medicine ‘Angelo Nocivelli’ and Department of Pediatrics, University of Brescia, Brescia, Italy

    V Lougaris, A Soresina, M Fiorini & A Plebani

  3. Department of Pediatrics, University of Torino, Torino, Italy

    S Martino

  4. Department of Pediatrics, Ospedale Bambino Gesù, Roma, Italy

    P Rossi

  5. Department of Pediatrics, University of Milano, Milano, Italy

    M C Pietrogrande

  6. Department of Pediatrics II, University of Bari, Bari, Italy

    B Martire

  7. Department of Immunology, University of Napoli ‘Federico II’, Napoli, Italy

    G Spadaro

  8. Department of Pediatrics I, University of Bari, Bari, Italy

    F Cardinale

  9. Department of Pediatrics, University of Cagliari, Cagliari, Italy

    F Cossu

  10. Department of Pediatrics, University of Ancona, Ancona, Italy

    P Pierani

  11. Department of Immunology, University of Roma ‘La Sapienza’, Roma, Italy

    I Quinti

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Correspondence to S Ferrari.

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Ferrari, S., Zuntini, R., Lougaris, V. et al. Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia. Genes Immun 8, 325–333 (2007). https://doi.org/10.1038/sj.gene.6364391

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  • DOI: https://doi.org/10.1038/sj.gene.6364391

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