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A number sign (#) is used with this entry because of evidence that autosomal recessive agammaglobulinemia-9 (AGM9) is caused by homozygous or compound heterozygous mutation in the SLC39A7 gene (601416) on chromosome 6p21.

Agammaglobulinemia-9 (AGM9) is an autosomal recessive primary immunodeficiency characterized by recurrent bacterial infections associated with agammaglobulinemia and absence of circulating B cells. Additional features include failure to thrive and skin involvement. The severity is variable: more severe cases may require hematopoietic stem cell transplantation, whereas others can be treated effectively with Ig replacement therapy (summary by Anzilotti et al., 2019).

For a discussion of genetic heterogeneity of autosomal agammaglobulinemia, see AGM1 (601495).

Anzilotti et al. (2019) reported 6 patients from 5 unrelated families with a primary immunodeficiency associated with agammaglobulinemia and absent circulating B cells. The patients, who ranged from 3.5 to 32 years of age, were of white European, South Asian, and Hispanic descent. Clinical details were limited, but all had recurrent bacterial infections. All had variable skin involvement, including blistering dermatosis, mild eczematous rash, seborrheic dermatitis, and transient necrotizing granulomatous rash. One individual (P4) had iron-deficiency anemia, vitamin D deficiency, enteropathy, and failure to thrive. Two sibs (P1 and P2) with the most severe phenotype with blistering dermatosis had failure to thrive and developed thrombocytopenia; P2 had profound sensorineural deafness. Bone marrow examination of P1 and P2 showed a progressive failure of B-cell development with an excess of pro-B cells relative to pre-B cells, and an even lower proportion of immature B cells relative to pre-B cells. T-cell numbers and function were normal in all patients. P1 and P2 underwent hematopoietic stem cell transplantation with resolution of symptoms. Other patients responded well to Ig replacement therapy.

The transmission pattern of AGM9 in the families reported by Anzilotti et al. (2019) was consistent with autosomal recessive inheritance.

In 6 patients from 5 unrelated families with AGM9, Anzilotti et al. (2019) identified compound heterozygous or homozygous mutations in the SLC39A7 gene (see, e.g., 601416.0001-601416.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variants were either absent from or present at a low frequency in the heterozygous state in gnomAD. Studies of patient cells and HEK293 cells transfected with the mutations showed that the mutant proteins were expressed normally and localized properly to the endoplasmic reticulum. However, Xenopus oocytes transfected with 2 of the mutations showed decreased zinc transporter activity compared to controls. Knockin mutant mouse models recapitulated the phenotype with a severe defect in B-cell development. The authors concluded that proper zinc dynamics is essential for proper B-cell development and that the disease alleles are likely hypomorphic with partial loss of SLC39A7 function.

Anzilotti et al. (2019) found that knockin mice carrying hypomorphic Slc39a7 mutations, including the P198A mutation (orthologous to the human P190A mutation, 601416.0001), demonstrated profound B-cell deficiency with variable growth and skin defects. Homozygosity for a null allele was embryonic lethal. Detailed studies of mutant mice with hypomorphic mutations showed impaired B-cell development affecting multiple development pathways. Other findings included decreased levels of cytoplasmic zinc, evidence of accelerated death of normal B cells, decreased phosphorylation of signaling molecules downstream of the pre-B cell and B-cell receptors (BCR), and defective signaling by the BCR during positive selection.