Figure 2. Novel STAT1 Mutations in Two Kindreds.

(A) STAT1 genotype and clinical phenotype of three kindreds. In kindred A, members I.1 and II.1 had tuberculosis, and III.2 and IV.1 (P1) had severe BCG disease. In kindred B, members I.1 and III. 2 (P2) were infected with M. tuberculosis and M. avium, respectively. Kindred C has been described elsewhere; II.2 (P3) developed disseminated BCG disease. Individuals with clinical disease caused by weakly virulent (BCG or M. avium) and more virulent (M. tuberculosis) mycobacteria are indicated in black and gray, respectively, and healthy individuals are shown in white. The index cases are indicated with an arrow. Genetically affected individuals (heterozygous for any of the three STAT1 mutations) with no clinical phenotype at the time of this study are indicated by a vertical line. Known STAT1 genotypes (WT, E320Q, Q463H, L706S) are indicated under each individual, with a question mark indicating unknown genotype.

(B) The human STAT1 coding region is shown, with its known pathogenic mutations. The coiled-coil domain (CC), DNA-binding domain (DNA-B), linker domain (L), SH2 domain (SH2), tail segment domain (TS), and trans-activator domain (TA) are indicated, together with their amino-acid boundaries. Tyrosine 701 (Y) is also indicated. Mutations in red are recessive mutations associated with complete STAT1 deficiency (due to a lack of STAT1 production), impaired IFNG-induced GAF activation and IFNA-induced ISGF3 activation, and a syndrome of predisposition to mycobacterial and severe viral disease in homozygous individuals. Mutations in green are associated, in heterozygous individuals, with partial STAT1 deficiency (normal STAT1 expression), impaired IFNG-induced GAS-binding activity but normal IFNA-induced ISRE-binding activity, and MSMD (predisposition to mycobacterial but not viral disease). Mutations reported for the first time in this study are indicated in italics.