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

TY - JOUR

T1 - Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.

AU - Zur Stadt, Udo

AU - Beutel, Karin

AU - Kolberg, Susanne

AU - Schneppenheim, Reinhard

AU - Kabisch, Hartmut

AU - Janka, Gritta

AU - Hennies, Hans Christian

N1 - 2005 Wiley-Liss, Inc.

PY - 2006/1

Y1 - 2006/1

N2 - 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.

AB - 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.

KW - Child

KW - Cohort Studies

KW - DNA Mutational Analysis

KW - Exons

KW - Humans

KW - Lymphohistiocytosis, Hemophagocytic

KW - Membrane Glycoproteins

KW - Membrane Proteins

KW - Mutation

KW - Nerve Tissue Proteins

KW - Perforin

KW - Pore Forming Cytotoxic Proteins

KW - Qa-SNARE Proteins

KW - rab GTP-Binding Proteins

U2 - 10.1002/humu.20274

DO - 10.1002/humu.20274

M3 - SCORING: Journal article

C2 - 16278825

VL - 27

SP - 62

EP - 68

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

IS - 1

M1 - 1

ER -