A novel mutation in SLC39A7 identified in a patient with autosomal recessive agammaglobulinemia: The impact of the J Project

Abstract

To the Editor, ZIP7 deficiency is the most recently described congenital agammaglobulinemia with autosomal recessive inheritance. 1 ZIP7, encoded by SLC39A7, is an endoplasmic reticulum-to-cytoplasm Zn 2+ transporter. Developing B cells are sensitive to altered Zn 2+ distribution, which causes developmental blockade beyond the pre-B cell stage. 2 Complete loss of ZIP7 in cell lines causes a reduction in cytoplasmic Zn 2+ and an increase in endoplasmic reticulum Zn 2+ concentration. Since the original report in 2019, no additional cases of ZIP7 deficiency have been published. Here, we describe a patient evaluated for recurrent respiratory tract infections, meningitis, agammaglobulinemia, and B cell lymphopenia, ultimately found to carry a novel SLC39A7 variant. We describe his clinical characteristics, immunological findings, and genetic investigations.We also report on the impact of the J Project (JP) in improving primary immunodeficiency (PID) patient care and research in Eastern and Central Europe (ECE).The patient and his family members were interviewed, examined, treated, and monitored at the University Clinic for Children's Disease in Skopje. Medical records were obtained from the electronic registry of the University Clinic. The mother of the patient has given written informed consent to conduct the study and for the publication of data. All procedures were performed in accordance with the ethical standards of the Institutional Research Committee.Genomic DNA from the patient and his family members was isolated with the Gen Elute Blood Genomic DNA kit (Sigma-Aldrich) and subjected to whole-exome sequencing (WES) in the patient and targeted gene sequencing in the patient and available family members. 3 WES was performed at the New York Genome Center and the Rockefeller University using an Illumina HiSeq 2500 sequencing system (Illumina). Exome capture was carried out with SureSelect human all exome kit (Agilent) in accordance with the manufacturer's instructions. Putative disease alleles found by WES were validated by dideoxy Sanger sequencing in the patient AND in family members. Exons and flanking intronic regions of SLC39A7 wereThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021

“…Thus, taken 10 countries (with the exception of Bosnia & Herzegovina, Montenegro and Kosovo), the cumulative number of patients increased from max 100 to 5307 by the end of 2021 ( Figure 1 ). A conceptual IEI-focused professional meeting series was started in 2004 and reached measurable results even in countries with low socioeconomic conditions including the Rep. of Moldova, Rep. of North Macedonia, Albania, and Kosovo ( 11 , 25 , 26 ). Over the past 18 years, 344 IEI-focused conferences were organized ( Supplementary Table 1 and Figure 2A ).…”

“…More than 450 IEIs have been described but many of them only in a few patients and families and data were obtained mostly from mice studies ( 7 – 11 ). Limitations to publish rare IEI cases in medical journals hamper the accumulation of substantial amount of clinical data.…”

A clinical case of autosomal recessive agammaglobulinemia with B-cell deficiency

“…Как следствие, дефекты самой структуры BCR, включая μ тяжелую цепь, суррогатные легкие цепи (VpreB и λ5), гены Igα (CD79) и Igβ (CD79B), которые образуют гетеродимерные трансмембранные сигнальные трансдукционные элементы, приводят к аутосомным формам агаммаглобулинемии. После BTK ген, кодирующий μ тяжелую цепь, IGHM (расположенный на хромосоме 14q32.33) является вторым наиболее часто мутируемым геном у пациентов с агаммаглобулинемией, но по-прежнему составляет лишь около 5 % пациентов [3,9].…”

Inborn errors of human B cell development, differentiation, and function

“…For instance, mutations disrupting Mg 2+ ( MAGT1 ) or Ca 2+ ( STIM1 , ORAI1 ) transport in lymphoid cells ( Vaeth and Feske, 2018 ) cause combined immunodeficiencies (CID) predominantly due to defects in functions of T cells and NK cells, rather than B cells ( Vaeth and Feske, 2018 ). Recently, the importance of zinc in B cell development was revealed by identifying seven individuals from six families with biallelic hypomorphic variants in SLC39A7 , encoding the zinc transporter ZIP7 ( Anzilotti et al, 2019 ; Erdős et al, 2022 ; Fig. 3 ).…”

“…All patients had recurrent bacterial infections, agammaglobulinemia, very few blood B cells, and a severe block at the pro → pre-stage of B cell development ( Fig. 1 ; Anzilotti et al, 2019 ; Erdős et al, 2022 ). By generating mice carrying patient hypomorphic Slc39a7 alleles, Anzilotti et al (2019) elegantly determined the causes of the selective B cell deficiency due to impaired ZIP7 function.…”