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Molecular Analysis of the Pre-BCR Complex in a Large Cohort of Patients Affected by Autosomal-Recessive Agammaglobulinemia

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Molecular Analysis of the Pre-BCR Complex in a Large Cohort of Patients Affected by Autosomal-Recessive Agammaglobulinemia Genes and Immunity (2007) 8, 325–333 & 2007 Nature Publishing Group All rights reserved 1466-4879/07 $30.00 www.nature.com/gene ORIGINAL ARTICLE Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia S Ferrari1, R Zuntini1, V Lougaris2, A Soresina2,VSˇourkova´1,12, M Fiorini2, S Martino3, P Rossi4, MC Pietrogrande5, B Martire6, G Spadaro7, F Cardinale8, F Cossu9, P Pierani10, I Quinti11, C Rossi1 and A Plebani2 1Medical Genetics Unit and CRBa, S.Orsola-Malpighi University Hospital, Bologna, Italy; 2Institute of Molecular Medicine ‘Angelo Nocivelli’ and Department of Pediatrics, University of Brescia, Brescia, Italy; 3Department of Pediatrics, University of Torino, Torino, Italy; 4Department of Pediatrics, Ospedale Bambino Gesu`, Roma, Italy; 5Department of Pediatrics, University of Milano, Milano, Italy; 6Department of Pediatrics II, University of Bari, Bari, Italy; 7Department of Immunology, University of Napoli ‘Federico II’, Napoli, Italy; 8Department of Pediatrics I, University of Bari, Bari, Italy; 9Department of Pediatrics, University of Cagliari, Cagliari, Italy; 10Department of Pediatrics, University of Ancona, Ancona, Italy and 11Department of Immunology, University of Roma ‘La Sapienza’, Roma, Italy 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 m heavy chain (mHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G4A nucleotide substitution at the À1 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 mHC and in the l5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology. Genes and Immunity (2007) 8, 325–333; doi:10.1038/sj.gene.6364391; published online 5 April 2007 Keywords: agammaglobulinemia; pre-BCR; mHC; IGHM mutations; human immunodeficiency Introduction the assembly of the mature B-cell receptor (BCR) – composed of mHC, light chain, and the Iga/Igb hetero- Early B-cell development is a highly regulated process, dimeric signal-transducing elements – and its expression taking place in the bone marrow. The transition from the on the surface of newly formed immature B cells.3 The pro-B-cell to the pre-B-cell stage is defined by sequential correct expression and signaling activity of the BCR are immunoglobulin gene rearrangements and surface ex- required for normal B-cell development. Accordingly, pression of the pre-B-cell receptor (pre-BCR) complex mutations in the genes required for BCR assembly or for containing the m heavy chain (mHC), Iga/Igb hetero- its signaling cascade, severely impair B-cell development 1 dimers and the surrogate light chains (SLC) (VpreB/l5). in the bone marrow, causing X-linked and autosomal- Various studies have investigated the different steps and recessive forms of agammaglobulinemia in humans, the transcription factors involved in this phase of B-cell characterized by low/absent serum immunoglobulin 2 development. The checkpoint at the pre-BCR level is levels and absence of circulating B cells.4 required for the following VJL rearrangement that allows Mutations in the gene coding for the Bruton tyrosine kinase (Btk), a cytoplasmic protein that mediates BCR Correspondence: Dr S Ferrari, Laboratorio di Genetica Medica, signaling, were found to be responsible for X-linked Policlinico S.Orsola-Malpighi – Pad.11, via Massarenti 9, 40138 agammaglobulinemia (XLA).5,6 In XLA, B-cell develop- Bologna, Italy. ment in the bone marrow is blocked at the pro-B- to pre- E-mail: [email protected] B-cell stage.7,8 However, even though XLA accounts for 12Current address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Praha. 85–90% of all cases of agammablobulinemia, a small Received 6 December 2006; revised and accepted 23 February 2007; group of patients have a block of B-cell development published online 5 April 2007 without evidence of BTK mutations. The family trees of Pre-BCR mutations in autosomal-recessive agammaglobulinemia S Ferrari et al 326 these patients are suggestive of an autosomal-recessive Table 1 Relevant features of the 23 patients included in this study form of agammaglobulinemia. The crucial role of BCR signaling for B-cell development and the phenotype of Patient Sex Age at IgG IgA IgM %B a b b b animal models point to the genes encoding for compo- diagnosis (mg/dl ) (mg/dl ) (mg/dl ) cells nents of the pre-BCR as promising candidate genes for autosomal-recessive forms of agammaglobulinemia. In P1 M 8 months 17 o6.5 1 o1 m P2 F 24 months 15 23 17 o1 fact, a mouse knockout model demonstrates that HC is P3 M 5 years 257 10 31 1–2 essential for B-cell development; lack of mHC causes P4 M 23 years 279 o6.5 12 o1 a specific block at the pro-B- to pre-B-cell stage and a P5 M 14 months 208 8 35 o1 severe reduction of B-cell number in the periphery.9 Four P6 F 10 years 297 13 14 1–2 point mutations, a 2-bp deletion and few large deletions P7 M 9 months 100 7 3 o1 of the human mHC gene (IGHM) have been identified P8 M 9 years 252 12 29 o1 previously by genetic analysis in patients with auto- P9 F 5 months 110 o6.5 11 o1 10,11 P10 M 24 months 150 20 38 1 somal-recessive forms of agammaglobulinemia. An- P11 F 9 months 18 o6.5 3 1–2 other member of the pre-BCR complex – the l5 gene – P12 M 6 months 179 8 11 o1 was also knocked out in the mouse, resulting in a leaky P13 M 5 years 20 o6.5 10 2 phenotype with a specific block at the pre-B-cell stage of P14 M 12 months 11 o6.5 5 1–2 differentiation; however, 4-months-old mice retain 20% P15 F 20 months o5 o6.5 o15 o1 of peripheral B cells and show a normal capability to P16 F 6 years 72 o6.5 4 1–2 P17 F 9 years ND o6.5 9 o1 mount an antibody response to both T-dependent and P18 F 31 years 41 o6.5 10 o1 12 T-independent antigens. In humans, a single case of P19 F 9 years 85 10 28 o1 compound heterozygote mutations in the l5/14.1 gene P20 M 4 months 42 o6.5 61 1–2 was associated with classical autosomal-recessive agam- P21 M 1 month ND o6.5 o18 o1 maglobulinemia,13 emphasizing the fact that mutations P22 F 16 months ND o6.5 o18 o1 in the same gene often affect B-cell development and P23 M 29 years 255 o6.5 25 o1 functionality to different extents in humans and mice. a Finally, knockout models of the last two components of Age at the time of the first immunoglobulin dosage. b the pre-BCR complex, CD79a and CD79b,14,15 provide Immunoglobulin reference ranges vary according to the age. evidence for their requirement in B-cell differentiation in Values used in our centers, 4–12 months: IgG 220–920, IgA 10–85, the bone marrow, in particular in the V-DJ rearrangement IgM 28–200; 13–36 months: IgG 365–1710, IgA 17–180, IgM 48–340; process. Recently, two patients were found to have 3–8 years: IgG 530–1960, IgA 37–315, IgM 49–290; 9–16 years: IgG 640–1920, IgA 60–300, IgM 59–200; 416 years: IgG 690–1500, IgA homozygous defects in Iga:16,17 comparison with mHC- 85–410, IgM 40–240. ND, not available before immunoglobulin deficient patients reveals, in both cases, a block at infusion. the early stages of B-cell development and similarly impaired V-DJ rearrangements.16 In this study, 23 Italian patients diagnosed with agammaglobulinemia (11 females and 12 males for whom mutations in BTK were excluded) were analyzed mia subregistry. The remaining seven male patients were for mutations in each of the genes encoding for the pre- excluded form this study because either deceased or BCR proteins. We identified one previously known untraceable. Patients previously subjected to similar mutation and two novel mutations in the coding region genetic screenings in other laboratories were excluded. of the IGHM gene and several new genetic polymor- Table 1 summarizes the main clinical features of these phisms (single nucleotide polymorphisms (SNPs)) in the patients, showing absent or nearly absent counts of IGHM and VpreB/l5 genes. circulating B cells. The genetic analysis was performed by polymerase chain reaction (PCR) amplification and direct DNA Results sequencing of all exons from the genes encoding the five proteins of the pre-BCR: six exons of mHC gene Patient selection (IGHM), three exons of l5-like gene (IGLL1), two exons of A total of 23 patients, from the Italian Association of VpreB gene (VpreB1), five exons of Iga gene (mb-1) and Pediatric Hematology and Oncology (AIEOP)-Italian six exons of Igb gene (B29).
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