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ZIP7, encoded by the zinc transporter gene SLC39A7, has been implicated in an autosomal recessive agammaglobulinemia phenotype characterized by absent B cells and early-onset infections in humans. A Nature Immunology study described five unrelated families with biallelic hypomorphic SLC39A7 variants presenting with absent B cells, agammaglobulinemia and recurrent infections (PMID:30718914). This yields a strong gene–disease association based on multiple probands, diverse variant types and concordant functional modeling.
Genetic evidence supports autosomal recessive inheritance with five probands carrying homozygous or compound heterozygous mutations. Variants include four missense alleles (c.1087G>A (p.Glu363Lys), c.568C>G (p.Pro190Ala), c.1184C>T (p.Thr395Ile), c.650T>C (p.Leu217Pro)) and one truncating allele (c.1114C>T (p.Gln372Ter)) identified across unrelated kindreds (PMID:30718914). Selected reported variant: c.568C>G (p.Pro190Ala).
Segregation analysis is consistent with recessive transmission in nuclear families; however, additional affected relatives beyond the index cases were not reported. The genetic spectrum and inheritance pattern satisfy strong ClinGen genetic criteria for a recessive immunodeficiency.
Functional models provide robust experimental concordance. CRISPR-Cas9–engineered hypomorphic alleles in mice recapitulated the human B cell developmental blockade and resulted in embryonic lethality for null alleles. Mutant B cells exhibited reduced cytoplasmic free zinc, increased phosphatase activity and diminished phosphorylation of key signaling intermediates downstream of the pre-B and B cell receptors, highlighting a zinc-dependent mechanism of B cell selection (PMID:30718914).
Additional mechanistic insights derive from a phenotypic chemical screen that identified ZIP7 as a direct target of the small molecule NVS-ZP7-4, where a V430E mutation conferred resistance and underscored the critical role of ER zinc homeostasis in lymphocyte signaling (PMID:30643281).
Together, the convergence of genetic, segregation and in vivo functional data support a Strong clinical validity classification for SLC39A7 in autosomal recessive Agammaglobulinemia. This association informs diagnostic sequencing panels and suggests that modulation of zinc transport may represent a therapeutic avenue for B cell immunodeficiency.
Gene–Disease AssociationStrong5 unrelated probands with biallelic SLC39A7 variants; concordant mouse model and functional data Genetic EvidenceStrongFive families with homozygous or compound heterozygous variants, including four missense and one truncating allele, consistent with autosomal recessive inheritance ([PMID:30718914]) Functional EvidenceStrongHypomorphic mouse models recapitulate human B cell developmental block; biochemical assays demonstrate disrupted zinc homeostasis and BCR signaling |