ClinVar

In 3 unrelated Pakistani children with familial hemophagocytic lymphohistiocytosis (FHL4; 603552), each born of consanguineous parents, Muller et al. (2014) identified a homozygous c.173T-C transition in the STX11 gene, resulting in a leu58-to-pro (L58P) substitution in the first alpha-helix of the conserved N-terminal Habc domain. All of the parents were unaffected and heterozygous for the mutation. Peripheral blood cells, including NK cells, from 1 of the patients showed significantly decreased STX11 protein levels compared to controls. In vitro functional expression studies in HEK293 cells showed that the mutant L58P protein was expressed, but did not bind to STXBP2 (601717). In contrast, the C-terminal Q268X mutant protein (605014.0003) did not show impaired binding to STXBP2. Muller et al. (2014) suggested that the impaired binding to STXBP2 may have led to degradation of the mutant L58P STX11 protein. The patients presented in infancy or early childhood with clinical and laboratory evidence of a hyperinflammatory state. Resting patient NK cells showed defective lytic activity and impaired degranulation. One of the patients also carried a heterozygous P271S variant in the UNC13D gene (608897) (frequency of 0.001 among Caucasians) and a homozygous R928C variant in the UNC13D gene (frequency of 0.01 among Caucasians); this patient had the earliest onset, at age 2 months. Two of the patients died in childhood, and the third was lost to follow-up.