An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2.
Familial hemophagocytic lymphohistiocytosis (FHL) is an often-fatal hyperinflammatory disorder caused by autosomal recessive mutations in PRF1, UNC13D, STX11, and STXBP2. We identified a homozygous STX11 mutation, c.173T > C (p.L58P), in three patients presenting clinically with hemophagocytic lymphohistiocytosis from unrelated Pakistani families. The mutation yields an amino acid substitution in the N-terminal Habc domain of syntaxin-11 and resulted in defective natural killer cell degranulation. Notably, syntaxin-11 expression was decreased in patient cells. However, in an ectopic expression system, syntaxin-11 L58P was expressed at levels comparable to wild-type syntaxin-11, but did not bind Munc18-2. Moreover, another N-terminal syntaxin-11 mutant, R4A, also did not bind Munc18-2. Thus, we have identified a novel missense STX11 mutation causative of FHL type 4. The syntaxin-11 R4A and L58P mutations reveal that both the N-terminus and Habc domain of syntaxin-11 are required for binding to Munc18-2, implying similarity to the dynamic binary binding of neuronal syntaxin-1 to Munc18-1.
Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm , Sweden.
Martha-Lena
ML
Müller
Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm , Sweden.
Samuel C C
SC
Chiang
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden ; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden.
Marie
M
Meeths
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden ; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden.
Bianca
B
Tesi
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden ; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden.
Miriam
M
Entesarian
Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden ; Science for Life Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm , Sweden.
Daniel
D
Nilsson
Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm , Sweden.
Stephanie M
SM
Wood
Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden.
Magnus
M
Nordenskjöld
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm , Sweden.
Jan-Inge
JI
Henter
Division of Hematology and Oncology, Hospital for Sick Children , Toronto, ON , Canada.
Ahmed
A
Naqvi
Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm , Sweden ; Broegelmann Research Laboratory, Institute of Clinical Sciences, University of Bergen , Bergen , Norway.
Yenan T
YT
Bryceson
Munc18-2; N-peptide; familial hemophagocytic lymphohistiocytosis; syntaxin-11