Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A

• Published in: Human mutation Vol. 27; no. 1; pp. 62 - 68
• Main Authors: Stadt, Udo Zur, Beutel, Karin, Kolberg, Susanne, Schneppenheim, Reinhard, Kabisch, Hartmut, Janka, Gritta, Hennies, Hans Christian
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2006; Hindawi Limited
• Subjects: Amino acids; Child; Chromosomes; Cohort Studies; Cytotoxicity; DNA Mutational Analysis; Exons - genetics; FHL; Hematology; hemophagocytic lymphohistiocytosis; hMunc13-4; Humans; Lymphohistiocytosis, Hemophagocytic - genetics; Membrane Glycoproteins - genetics; Membrane Proteins - genetics; Mutation; Mutation - genetics; Nerve Tissue Proteins - genetics; Oncology; Pediatrics; Perforin; Pore Forming Cytotoxic Proteins - genetics; Qa-SNARE Proteins - genetics; rab GTP-Binding Proteins - genetics; rab27 GTP-Binding Proteins; syntaxin 11; Germany; Turkey
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.20274

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal‐recessive disease that affects young children. It presents as a severe hyperinflammatory syndrome with activated macrophages and T lymphocytes. Mutations in the perforin 1 gene (PRF1) were found in FHL‐2 in 15–50% of all cases. Defective granule exocytosis caused by mutations in the hMunc13‐4 gene (UNC13D) has been described in FHL‐3. FHL‐4 patients have mutations in STX11, a t‐SNARE involved in intracellular trafficking. We analyzed a large group of 63 unrelated patients with FHL of different geographic origins (Turkey:32; Germany:23; others:8) for mutations in STX11, PRF1, and UNC13D. We identified mutations in 38 samples (20 in PRF1, 12 in UNC13D, and six in STX11). Of 32 patients from Turkey, 14 had mutations in PRF1, six had mutations in UNC13D, and six had mutations in STX11. The mutation Trp374X in PRF1 was found in 12 patients from Turkey and was associated with a very early onset of the disease below the age of 3 months in all cases. In contrast, three of 23 and four of 23 patients from Germany, and three of eight and two of eight from other origins showed mutations in PRF1 and UNC13D, respectively, but none in STX11. Thus, FHL‐2, FHL‐3, and FHL‐4 account for 80% of the HLH cases of Turkish origin, and for 30% of German patients. Furthermore, we identified mutations in RAB27A in three patients with FHL‐related Griscelli syndrome type 2. In functional studies using a mammalian two‐hybrid system we found that missense mutations Ala87Pro in Rab27a and Leu403Pro in hMunc13‐4 each prevented the formation of a stable hMunc13‐4/Rab27a complex in vitro. Our findings demonstrate extensive genetic and allelic heterogeneity in FHL and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D. Hum Mutat 27(1),62–68, 2005. © 2005 Wiley‐Liss, Inc.