4.5 Article

Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations

Journal

INTERNATIONAL IMMUNOLOGY
Volume 32, Issue 10, Pages 663-671

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxaa043

Keywords

mycobacteria; primary immunodeficiency; target RNA sequence; virus

Categories

Funding

  1. Japan Society for the Promotion of Science [18KK0228, 16H05355, 19H03620]
  2. Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development (AMED)
  3. Grants-in-Aid for Scientific Research [19H03620, 18KK0228, 16H05355] Funding Source: KAKEN

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Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T>G and c.542-8 A>G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient's cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-gamma and IFN-alpha. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations.Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.

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