Immunodeficiency 22

A number sign (#) is used with this entry because of evidence that immunodeficiency-22 (IMD22) is caused by homozygous mutation in the LCK gene (153390) on chromosome 1p35. One such patient has been reported.

Clinical Features

Goldman et al. (1998) described an infant with clinical and laboratory features of severe combined immunodeficiency (SCID) and selective CD4 lymphopenia and lack of CD28 expression on CD8+ T cells. The patient presented in the first months of life with severe diarrhea, oral candidiasis, and failure to thrive. Rotavirus was isolated from the stool, Enterobacter cloacae from the blood, and cytomegalovirus from the urine and intestinal biopsies. The patient was found to have lymphopenia and hypogammaglobulinemia, and underwent bone marrow transplant at age 32 months. Immunologic workup indicated that patient T cells showed a poor response to T-cell receptor (TCR) antigens, including mitogens and IL2 (147680). However, more proximal T-cell antigen receptor signaling events, such as anti-CD3 induced protein-tyrosine phosphorylation, phosphorylation of mitogen-associated protein kinase, and calcium mobilization, were intact. Although p59(fyn) (FYN; 137025) and ZAP70 (176947) were normal, there was a marked decrease in the level of LCK.

Sawabe et al. (2001) reported a 22-year-old Japanese male with a mild form of immunodeficiency found on evaluation of hilar lymphadenopathy. He had relative CD4+ T-cell lymphopenia and hypogammaglobulinemia, suggesting a defect in helper T cells. Proliferative responses to mitogens were impaired.

Hauck et al. (2012) reported a French girl, conceived by in vitro fertilization, with primary immunodeficiency due to T-cell dysfunction. She presented at age 15 months with recurrent respiratory infections and a history of protracted diarrhea, resulting in failure to thrive. She later developed fever spikes, nodular skin lesions, and inflammation of the interphalangeal joints. Skin biopsy showed cellular inflammatory infiltrate and neutrophilic panniculitis with necrosis and abscesses. At about 2 years of age, she developed ascites and pericarditis with capillary leak syndrome and retinal vasculitis. At age 29 months, she had anemia and thrombocytopenia with antiplatelet antibodies. She died at age 30 months after undergoing hematopoietic stem cell transplantation. Immunologic workup showed profound CD4+ T-cell lymphopenia, but these cells had a central memory phenotype. CD8+ T cells were exhausted effector memory cells. Most of the CD4+ and CD8+ T cells were CD95+, suggesting that they had been activated, whereas control cells showed a mix of naive and activated markers. Patient T cells also showed reduced surface expression of CD4 and CD8 compared to controls and impaired proliferative response to CD3 stimulation. Tyrosine phosphorylated substrates of TCR activation were markedly lower in patient cells compared to control. These findings were consistent with T-cell immunodeficiency due to a T-cell signaling defect. Numbers of B cells and natural killer cells were normal or slightly low. Immunoglobulins were normal, but response to vaccination was low. Multiple autoantibodies were detected.

Inheritance

The transmission pattern of IMD22 in the family reported by Hauck et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an infant with T-cell deficiency and decreased LCK, Goldman et al. (1998) found absence of exon 7 in LCK transcripts. Genetic analysis indicated that this was an alternatively spliced LCK transcript lacking the exon 7 kinase-encoding domain, although no pathogenic mutation was found in the LCK gene. These data suggested that deficiency in p56(lck) expression can produce a SCID phenotype in humans. In a Japanese man with a similar, but much milder, immunologic abnormality as that described by Goldman et al. (1998), Sawabe et al. (2001) found the same splicing abnormality affecting exon 7 of the LCK gene. However, no mutations were found in the LCK sequence around exon 7. Western blot analysis demonstrated that the levels of LCK in the patient were reduced by approximately 40% compared to controls.

In a girl with immunodeficiency-22, Hauck et al. (2012) identified a homozygous missense mutation in the LCK gene (L341P; 153390.0001). Western blot analysis of patient cells showed decreased levels of mutant LCK. The mutant protein had no kinase activity and failed to reconstitute TCR signaling in LCK-deficient cells, consistent with a loss of function.