Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reticular dysgenesis is an autosomal recessive form of human severe combined immunodeficiency characterized by an early differentiation arrest in the myeloid lineage and impaired lymphoid maturation. In addition, affected newborns have bilateral sensorineural deafness. Here we identify biallelic mutations in AK2 (adenylate kinase 2) in seven individuals affected with reticular dysgenesis. These mutations result in absent or strongly decreased protein expression. We then demonstrate that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Last, we establish that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation of the sensorineural deafness in these individuals. These results identify a previously unknown mechanism involved in regulation of hematopoietic cell differentiation and in one of the most severe human immunodeficiency syndromes.
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PMID:Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. 1904 16

Human severe combined immunodeficiencies (SCID) are phenotypically and genotypically heterogeneous diseases. Reticular dysgenesis is the most severe form of inborn SCID. It is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal. These features exclude a defect in hematopoietic stem cells but point to a unique aberration of the myelo-lymphoid lineages. The dramatic clinical course of reticular dysgenesis and its unique hematological phenotype have spurred interest in the unknown genetic basis of this syndrome. Here we show that the gene encoding the mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2) is mutated in individuals with reticular dysgenesis. Knockdown of zebrafish ak2 also leads to aberrant leukocyte development, stressing the evolutionarily conserved role of AK2. Our results provide in vivo evidence for AK2 selectivity in leukocyte differentiation. These observations suggest that reticular dysgenesis is the first example of a human immunodeficiency syndrome that is causally linked to energy metabolism and that can therefore be classified as a mitochondriopathy.
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PMID:Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. 1904 17

Reticular Dysgenesis is a rare immunodeficiency which is clinically characterized by the combination of Severe Combined Immunodeficiency (SCID) with agranulocytosis and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 (AK2) were identified to cause this phenotype. In this review, we will demonstrate important clinical differences between reticular dysgenesis and other SCID entities and summarize recent concepts in the understanding of the pathophysiology of the disease and the management strategies for this difficult condition.
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PMID:Recent advances in understanding the pathogenesis and management of reticular dysgenesis. 2927 Sep 83