Immunodeficiency 44D81.9

Immunodeficiency-44 is an autosomal recessive primary immunodeficiency characterized in some patients by increased susceptibility to viral infections and adverse multisystemic responses to vaccination. Affected individuals appear to have defects in mitochondrial fission and fusion.

In five affected members of a consanguineous relationship with IMD44, Hambleton et al (2013) identified a homozygous splice site mutation in the STAT2 gene (600556.0001). No STAT2 protein was detectable in patient fibroblasts. In vitro studies of patient fibroblasts showed increased susceptibility to viral infection and complete failure of type I interferon response.

In two siblings with IMD44, Shahni et al (2015) identified a homozygous nonsense mutation in the STAT2 gene (C612X; 600556.0002). The mutation, found by a combination of homozygosity mapping and whole-exome sequencing, segregates with the disorder in the family. The patient's skeletal muscle and fibroblasts exhibited dense, elongated mitochondria. Knockdown of STAT2 in control cells resulted in a fourfold increase in mitochondrial length. The patient's fibroblasts exhibited undetectable STAT2 protein levels. Furthermore, increased levels of several outer and inner mitochondrial membrane fusion proteins were detectable, such as MFN1 (608506), MFN2 (608507), and OPA1 (605290), consistent with an increase in mitochondrial mass. Phosphorylation of STAT1 (600555) was also impaired, confirming disruption of the alpha-interferon pathway. STAT2-deficient patient cells showed decreased apoptosis in response to alpha-interferon compared with control subjects. The report suggests a link between innate immunity and mitochondrial dysfunction.

1. Hambleton Set al.(2013) STAT2 deficiency and susceptibility to viral illness in humans. Proc Nat Acad Sci 110: 3053-3058.
2. Shahni R et al. (2015) Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission. Brain 138: 2834-2846.