STXBP2 mutations in children with Familial Hemophagocytic Lymphohistiocytosis type 5

Valentina Cetica (1) , Alessandra Santoro (2) , Kimberly Gilmour (3) , Elena Sieni (1) , Daniela Pende (4) , Stefania Marcenaro (5) , Florian Koch (6) , Samantha Grieve (7) , Rachel Wheeler (3) , Roseanne Zhao (7) , Udo Zur Stadt (8) , Gillian M Griffiths (7) , Maurizio Arico' (1)

1 Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence
2 Ematologia A.O. Cervello Villa Sofia, Palermo
3 Centre for Immunodeficiency, Great Ormond Street Hospital, London
4 Istituto Nazionale per la Ricerca sul Cancro, Genoa
5 UniGe - Università degli studi di Genova = University of Genoa
6 Research Institute Children's Cancer Center, Hamburg, Germany
7 Addenbrooke's Hospital
8 University of Hamburg

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with uncontrolled inflammation; the clinical course usually starts within the first years of life, and is usually fatal unless promptly treated and then cured with haematopoietic stem cell transplant. FHL is caused by genetic mutations resulting in defective cell cytotoxicity; three disease related genes have been identified to date: perforin, Munc13-4 and syntaxin-11. A fourth gene, STXBP2, has been identified very recently as responsible for a defect in Munc18-2 in FHL-5. We describe the result of screening 28 families with HLH with previously unassigned genetic defects: 4 (14%) families originating from Italy, England, Kuwait and Pakistan with biallelic STXBP2 mutations were identified. The p.Pro477Leu resulting from c.1430C>T, and p.Arg405Gln resulting from the single c.1214G>A nucleotide change are known, while we contribute two novel mutations: p.Glu132Ala resulting from c.395A>C, and p.Gly541Ser, resulting from c.1621G>A. The detrimental effect of the p.Gly541Ser mutation was documented biochemically and functionally in NK and CD8 cells. Additional polymorphisms are also described. These data expand current knowledge on the genetic heterogeneity of FHL and suggest that patients with FHL5 may have different results in degranulation assays under different conditions.

Mots clés: Molecular genetics; Haematology (incl Blood transfusion)

Valentina Cetica, Alessandra Santoro, Kimberly Gilmour, Elena Sieni, Daniela Pende, et al.. STXBP2 mutations in children with Familial Hemophagocytic Lymphohistiocytosis type 5. Journal of Medical Genetics, 2010, 47 (9), pp.595. ⟨10.1136/jmg.2009.075341⟩. ⟨hal-00559606⟩