A number sign (#) is used with this entry because of evidence that immunodeficiency-55 (IMD55) is caused by compound heterozygous mutation in the GINS1 gene (610608) on chromosome 20p11.

Immunodeficiency-55 is an autosomal recessive primary immunodeficiency characterized by intrauterine growth retardation, natural killer (NK) cell deficiency, and chronic neutropenia. Most patients also have postnatal growth retardation. Other clinical manifestations include mild facial dysmorphism, dry or eczematous skin, and recurrent infections with both viruses and bacteria. The disorder appears to result from a defect in DNA replication causing blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells (summary by Cottineau et al., 2017).

Bernard et al. (2004) reported 2 French sisters, born of unrelated parents, with NK cell deficiency. The older child died from cytomegalovirus (CMV) infection at age 18 months, whereas the second child remained healthy at age 7 years and had a persistent lack of NK cells with no diagnosed viral infection. Both also had neutropenia, facial dysmorphism, and severe intrauterine growth retardation. One patient had transient T-cell lymphopenia. Eidenschenk et al. (2006) performed biochemical studies of peripheral immunologic cells derived from 1 of the patients reported by Bernard et al. (2004). Although NK cells could not be studied, T lymphocytes displayed excessive apoptosis, and T-cell blasts showed poor survival upon treatment with IL2 (147680) and IL15 (600554). The data suggested that an impaired survival response to IL2 and IL15 may account for the persistent lack of NK cells and transient CD8 T lymphopenia.

Cottineau et al. (2017) reported 3 unrelated patients, aged 7, 18, and 27 years, with IMD55. They also reviewed the sisters reported by Bernard et al. (2004). All 5 patients had severe intrauterine growth retardation, and 4 of the 5 patients showed postnatal growth deficiency; postnatal growth in patient 4 (P4) was reportedly normal. All had recurrent infections, both viral and bacterial, since early childhood. Several of the infections were severe, including CMV-positive respiratory tract infection and lung disease causing bronchiectasis, fibrosis, and respiratory failure (P1); varicella zoster (VZV) infection, several severe airway infections with adenovirus and respiratory syncytial virus (RSV) requiring hospitalization, and multiple episodes of diarrhea and gastroenteritis (P3); and necrotizing varicella and herpes simplex infections, folliculitis, and fungal infections (P4 and P5). Other features included lymphadenopathy, mild facial dysmorphism, and skin abnormalities such as eczema, atopic dermatitis, erythroderma, and ichthyosis. One patient developed an osteosarcoma possibly related to treatment with growth hormone, another patient had protein-losing enteropathy, hypothyroidism, and some features of premature aging, and another patient had autoimmune hemolytic anemia and progressive glaucoma resulting in blindness. Laboratory studies showed an almost complete lack of circulating NK cells, affecting both the CD56 bright and CD56 dim subsets, low or normal numbers of circulating T and B lymphocytes, and chronic neutropenia. There was no increase in the proliferation of NK cells in response to cytokine treatment in vitro, although neutrophil levels did respond to cytokine treatment and were sometimes normal during infection. Certain additional innate lymphocyte cell populations were also decreased, and some patients had decreased IgM and IgG. Bone marrow analysis showed variable abnormalities, including reduced myelopoiesis, erythroid dysplasia, dysmyelopoiesis, and myelodysplasia. There was a low proportion of metamyelocytes and neutrophils, suggesting a deficiency in the cell cycle and maintenance of neutrophil progenitors. None of the patients had autoantibodies.

The transmission pattern of IMD55 in the families reported by Cottineau et al. (2017) was consistent with autosomal recessive inheritance.

In 5 patients from 4 unrelated families with IMD55, Cottineau et al. (2017) identified compound heterozygous mutations in the GINS1 gene (610608.0001-610608.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Two of the mutations occurred in the 5-prime untranslated region and were demonstrated to cause splicing abnormalities with decreased GINS1 mRNA levels in patient cells. Cells from patients had lower GINS1 protein levels than control cells (40% on average; range, 29-53%), suggesting that both the UTR and missense mutations affected protein levels. Residual full-length wildtype GINS1 mRNA (5-10%) was also detected, consistent with 'leaky' or hypomorphic alleles, and likely explained why the patients survived, since knockdown of the GINS1 gene in mice is embryonic lethal. GINS1 activity ranged from 3 to 16%, depending on the GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. Patient cells showed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which could be rescued by wildtype GINS1. The findings suggested that GINS1 is critical for proper DNA replication and maintenance, particularly in NK cells.