A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency

Abstract

Background: Recombination-activating gene 1 (RAG1) deficiency presents with a varied spectrum of combined immunodeficiency, ranging from a T(-)B(-)NK(+) type of disease to a T(+)B(+)NK(+) phenotype.

Objective: We sought to assess the genetic background of patients with common variable immunodeficiency (CVID).

Methods: A patient given a diagnosis of CVID, who was born to a consanguineous family and thus would be expected to show an autosomal recessive inheritance, was subjected to clinical evaluation, immunologic assays, homozygosity gene mapping, exome sequencing, Sanger sequencing, and functional analysis.

Results: The 14-year-old patient, who had liver granuloma, extranodal marginal zone B-cell lymphoma, and autoimmune neutropenia, presented with a clinical picture resembling CVID. Genetic analysis of this patient showed a homozygous hypomorphic RAG1 mutation (c.1073 G>A, p.C358Y) with a residual functional capacity of 48% of wild-type protein.

Conclusion: Our finding broadens the range of disorders associated with RAG1 mutations and might have important therapeutic implications.

Keywords: Common variable immunodeficiency; differential diagnosis; granulomatous lesion; mismanagement; recombination activation genes.

Figure 1

Pedigree and mutation analysis of a RAG1 deficient patient presenting as CVID (shown by arrow)

Figure 2

A-Mul transformed Rag1^−/− murine pro-B cell line was first transduced with a retrovirus carrying a single copy of INV V(D)J substrate containing an inverted GFP flanked by RSS. A clone with a single integrant was selected and transduced with a retrovirus co-expressing either human wild-type (WT) RAG1 and human CD2 (hCD2), mutant C358Y RAG1 and hCD2, or just hCD2. V(D)J recombination activity of the C358Y mutant was calculated by measuring GFP expression, normalized to what observed in the presence of WT RAG1. One representative experiment of three is shown.

Figure 3

The location of RAG1 mutation in patients with leaky SCID and a granulomatous phenotype by compound heterozygous (P1–P4) and homozygous mutations (P5–P7, New P). CC: catalytic core, NBD: nanomer binding domain, UL: Ubiquitin ligase activity, HD: Homeodomain^{, , –,}