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Janinge Henter - One of the best experts on this subject based on the ideXlab platform.
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Haploinsufficiency of UNC13D increases the risk of lymphoma
Cancer, 2019Co-Authors: Alexandra Löfstedt, Bianca Tesi, Yenan T. Bryceson, Magnus Nordenskjold, Janinge Henter, Clas Ahlm, Ingvar A. Bergdahl, Marie MeethsAbstract:BACKGROUND: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity i ...
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An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2.
Frontiers in immunology, 2014Co-Authors: Martha-lena Müller, Bianca Tesi, Marie Meeths, Samuel C. C. Chiang, Stephanie M. Wood, Miriam Entesarian, Magnus Nordenskjold, Janinge Henter, Daniel Nilsson, Ahmed NaqviAbstract: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 NK 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.
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characterization of prf1 stx11 and UNC13D genotype phenotype correlations in familial hemophagocytic lymphohistiocytosis
British Journal of Haematology, 2008Co-Authors: Annacarin Horne, Eva Rudd, Chengyun Zheng, Kim Ramme, Aytemiz Gurgey, Yasser Wali, Zakia Allamki, Nevin Yalman, Magnus Nordenskjold, Janinge HenterAbstract:SummaryFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomalrecessive lethal condition characterized by fever, cytopenia,hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defectapoptosis triggering and lymphocyte cellular cytotoxicity. Thus far threedisease-causing genes (PRF1, UNC13D, STX11) have been identified. Weperformed a genotype-phenotype study in a large, multi-ethnic cohort of 76FHL patients originating from 65 unrelated families. Biallelic mutations inPRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%)and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed forall three genes, no molecular diagnosis was established. STX11 mutationswere most common in Turkish families (7/28, 25%), whereas in Middle Eastfamilies, PRF1 mutations were most frequent (6/13, 46%). No biallelicmutation was identified in most families of Nordic origin (13/14, 93%).Patients carrying PRF1 mutations had higher risk of early onset (age<6 months) compared to patients carrying STX11 mutations [adjusted oddsratio 8AE23 (95% confidence interval [CI] = 1AE20–56AE40), P =0AE032].Moreover, patients without identified mutations had increased risk ofpathological cerebrospinal fluid (CSF) at diagnosis compared to patients withSTX11 mutations [adjusted odds ratio 26AE37 (CI = 1AE90–366AE82), P =0AE015].These results indicate that the disease-causing mutations in FHL havedifferent phenotypes with regard to ethnic origin, age at onset, andpathological CSF at diagnosis.Keywords: familial hemophagocytic lymphohistiocytosis, phenotype, PRF1,UNC13D, STX11.
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Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis
British journal of haematology, 2008Co-Authors: Annacarin Horne, Eva Rudd, Chengyun Zheng, Kim Ramme, Aytemiz Gurgey, Yasser Wali, Nevin Yalman, Magnus Nordenskjold, Zakia Al-lamki, Janinge HenterAbstract:SummaryFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomalrecessive lethal condition characterized by fever, cytopenia,hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defectapoptosis triggering and lymphocyte cellular cytotoxicity. Thus far threedisease-causing genes (PRF1, UNC13D, STX11) have been identified. Weperformed a genotype-phenotype study in a large, multi-ethnic cohort of 76FHL patients originating from 65 unrelated families. Biallelic mutations inPRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%)and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed forall three genes, no molecular diagnosis was established. STX11 mutationswere most common in Turkish families (7/28, 25%), whereas in Middle Eastfamilies, PRF1 mutations were most frequent (6/13, 46%). No biallelicmutation was identified in most families of Nordic origin (13/14, 93%).Patients carrying PRF1 mutations had higher risk of early onset (age
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Severe bacteria-associated hemophagocytic lymphohistiocytosis in an extremely premature infant.
Acta paediatrica (Oslo Norway : 1992), 2007Co-Authors: Josefine Edner, Eva Rudd, Chengyun Zheng, Andreas Dahlander, Staffan Eksborg, E. Marion Schneider, Ann Edner, Janinge HenterAbstract:Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report an extremely premature girl, born in the 24th gestational week (BW 732 g), that during her second month developed a severe HLH subsequent to a Serratia marcescens septicemia, with hepatosplenomegaly, cytopenias, hyperbilirubinemia (mostly conjugated, total bilirubin 916 mumol/L), hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (21266 mug/L), and elevated sIL-2 receptor levels. Genetic analysis revealed no PRF1, STX11 or UNC13D gene mutations. Treatment was provided according to the HLH-2004 protocol with etoposide, dexamethasone, and immunoglobulin, but no cyclosporin because of immature kidneys. She recovered fully from the HLH but developed a severe retinopathy as well as green teeth secondary to the hyperbilirubinemia. We conclude that secondary, bacteria-associated HLH can develop in premature infants, and that HLH can be treated with cytotoxic therapy also in premature infants. It is important to be aware of HLH in premature infants, since it is treatable.
Bryce A. Binstadt - One of the best experts on this subject based on the ideXlab platform.
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Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis.
Arthritis and rheumatism, 2008Co-Authors: Melissa M. Hazen, Alexei A. Grom, Amy L. Woodward, Inga Hofmann, Barbara A. Degar, Alexandra H. Filipovich, Bryce A. BinstadtAbstract:The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13-4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH-associated genes in patients with systemic JIA have not been reported. We report the case of an 8-year-old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.
Aytemiz Gurgey - One of the best experts on this subject based on the ideXlab platform.
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Defective UNC13D gene-associated familial hemophagocytic lymphohistiocytosis triggered by visceral leishmaniasis: a diagnostic challenge.
Journal of pediatric hematology oncology, 2014Co-Authors: Gunay Balta, Fatih M Azik, Aytemiz GurgeyAbstract:Visceral leishmaniasis (VL) triggered genetic hemophagocytic lymphohistiocytosis (HLH) is clinically challenging. One-year-old VL-HLH patient improved after liposomal-amphotericin-B therapy, but subsequently deteriorated, although bone marrow amastigotes disappeared. Symptoms resolved after 8 weeks of HLH-2004 therapy but recurred upon cessation. Homozygous UNC13D gene 627delT mutation was identified however stem cell donor was unavailable. The patient died at age 4 years after central nervous system attacks and HLH recurrences. VL in HLH patients does not exclude a genetic etiology and requires structured clinical management. VL should be excluded in all HLH patients in endemic regions before immunochemotherapy, which is recommended for VL-HLH patients unresponsive to VL treatment and/or reactivated.
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Defective UNC13D gene-associated familial hemophagocytic lymphohistiocytosis triggered by visceral leishmaniasis: a diagnostic challenge.
Journal of Pediatric Hematology Oncology, 2014Co-Authors: Gunay Balta, Fatih M Azik, Aytemiz GurgeyAbstract:BACKGROUND Visceral leishmaniasis (VL) triggered genetic hemophagocytic lymphohistiocytosis (HLH) is clinically challenging. OBSERVATIONS One-year-old VL-HLH patient improved after liposomal-amphotericin-B therapy, but subsequently deteriorated, although bone marrow amastigotes disappeared. Symptoms resolved after 8 weeks of HLH-2004 therapy but recurred upon cessation. Homozygous UNC13D gene 627delT mutation was identified however stem cell donor was unavailable. The patient died at age 4 years after central nervous system attacks and HLH recurrences. CONCLUSIONS VL in HLH patients does not exclude a genetic etiology and requires structured clinical management. VL should be excluded in all HLH patients in endemic regions before immunochemotherapy, which is recommended for VL-HLH patients unresponsive to VL treatment and/or reactivated.
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characterization of prf1 stx11 and UNC13D genotype phenotype correlations in familial hemophagocytic lymphohistiocytosis
British Journal of Haematology, 2008Co-Authors: Annacarin Horne, Eva Rudd, Chengyun Zheng, Kim Ramme, Aytemiz Gurgey, Yasser Wali, Zakia Allamki, Nevin Yalman, Magnus Nordenskjold, Janinge HenterAbstract:SummaryFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomalrecessive lethal condition characterized by fever, cytopenia,hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defectapoptosis triggering and lymphocyte cellular cytotoxicity. Thus far threedisease-causing genes (PRF1, UNC13D, STX11) have been identified. Weperformed a genotype-phenotype study in a large, multi-ethnic cohort of 76FHL patients originating from 65 unrelated families. Biallelic mutations inPRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%)and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed forall three genes, no molecular diagnosis was established. STX11 mutationswere most common in Turkish families (7/28, 25%), whereas in Middle Eastfamilies, PRF1 mutations were most frequent (6/13, 46%). No biallelicmutation was identified in most families of Nordic origin (13/14, 93%).Patients carrying PRF1 mutations had higher risk of early onset (age<6 months) compared to patients carrying STX11 mutations [adjusted oddsratio 8AE23 (95% confidence interval [CI] = 1AE20–56AE40), P =0AE032].Moreover, patients without identified mutations had increased risk ofpathological cerebrospinal fluid (CSF) at diagnosis compared to patients withSTX11 mutations [adjusted odds ratio 26AE37 (CI = 1AE90–366AE82), P =0AE015].These results indicate that the disease-causing mutations in FHL havedifferent phenotypes with regard to ethnic origin, age at onset, andpathological CSF at diagnosis.Keywords: familial hemophagocytic lymphohistiocytosis, phenotype, PRF1,UNC13D, STX11.
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Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis
British journal of haematology, 2008Co-Authors: Annacarin Horne, Eva Rudd, Chengyun Zheng, Kim Ramme, Aytemiz Gurgey, Yasser Wali, Nevin Yalman, Magnus Nordenskjold, Zakia Al-lamki, Janinge HenterAbstract:SummaryFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomalrecessive lethal condition characterized by fever, cytopenia,hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defectapoptosis triggering and lymphocyte cellular cytotoxicity. Thus far threedisease-causing genes (PRF1, UNC13D, STX11) have been identified. Weperformed a genotype-phenotype study in a large, multi-ethnic cohort of 76FHL patients originating from 65 unrelated families. Biallelic mutations inPRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%)and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed forall three genes, no molecular diagnosis was established. STX11 mutationswere most common in Turkish families (7/28, 25%), whereas in Middle Eastfamilies, PRF1 mutations were most frequent (6/13, 46%). No biallelicmutation was identified in most families of Nordic origin (13/14, 93%).Patients carrying PRF1 mutations had higher risk of early onset (age
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Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis
Journal of medical genetics, 2007Co-Authors: Eva Rudd, Yenan T. Bryceson, Stephanie M. Wood, Chengyun Zheng, Josefine Edner, Kim Ramme, Sofie Gavhed, Aytemiz Gurgey, Marit Hellebostad, Annegrete BechensteenAbstract:Objective: Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin ( PRF1 ), syntaxin-11 ( STX11 ), and Munc13-4 ( UNC13D ). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort. Methods: Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded. Results: We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11 -negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset. Conclusions: Biallelic UNC13D mutations were found in 18% of the PRF1/STX11 -negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and/or CNS symptoms.
Karin Beutel - One of the best experts on this subject based on the ideXlab platform.
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Genotypeephenotype study of familial haemophagocytic lymphohistiocytosis type 3
2017Co-Authors: Elena Sieni, Valentina Cetica, Benedetta Ciambotti, Marie Meeths, Alessandra Santoro, Karin Beutel, Elena Mastrodicasa, Francesca Brugnolo, Daniela Pende, Lorenzo MorettaAbstract:Background Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898). Objective To carry out a genotypeephenotype study of patients with FHL3. Methods A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database.
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GENOTYPE-PHENOTYPE STUDY OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TYPE 3
Journal of Medical Genetics, 2011Co-Authors: Elena Sieni, Valentina Cetica, Benedetta Ciambotti, Marie Meeths, Alessandra Santoro, Karin Beutel, Elena Mastrodicasa, Francesca Brugnolo, Udo Zur Stadt, Daniela PendeAbstract:Background: Mutations of UNC13D are causative for FHL3 (OMIM 608898). We present a genotype-phenotype study of 845 FHL3 patients. Methods: A consortium of 3 countries planned to pool in a common database data on presenting features and mutations from individual patients with biallelic UNC13D mutations. Results: 845 FHL3 patients (median age: 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=123). Their ethnic origin was: Caucasian, n=57, Turkish, n=10, Asian, n=7, Hispanic, n=4, African, n=3 (not reported, n=34). Thrombocytopenia was present in 96%, splenomegaly in 95%, fever in 89%. Central nervous system was involved in 49/812 (60%) patients versus 36% in FHL2 (p=0.001). The combination of fever, splenomegaly, thrombocytopenia and hyperferritinemia was present in 71%. CD107a expression, NK activity and Munc13-4 protein expression were absent or reduced in all but one of the evaluated patients. We observed 54 different mutations, including 15 novel ones: 19 missense, 14 deletions or insertions, 12 nonsense, 911 splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p
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Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis type 3
Journal of medical genetics, 2011Co-Authors: Elena Sieni, Valentina Cetica, Benedetta Ciambotti, Marie Meeths, Alessandra Santoro, Karin Beutel, Elena Mastrodicasa, Francesca Brugnolo, Udo Zur Stadt, Daniela PendeAbstract:Background Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898). Objective To carry out a genotype–phenotype study of patients with FHL3. Methods A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database. Results 84 patients with FHL3 (median age 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=12). Their ethnic origin was Caucasian (n=57), Turkish (n=10), Asian (n=7), Hispanic (n=4), African (n=3) (not reported (n=3)). Thrombocytopenia was present in 94%, splenomegaly in 96%, fever in 89%. The central nervous system (CNS) was involved in 49/81 (60%) patients versus 36% in patients with FHL2 (p=0.001). A combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia was present in 71%. CD107a expression, NK activity and Munc 13-4 protein expression were absent or reduced in all but one of the evaluated patients. 54 different mutations were observed, including 15 new ones: 19 missense, 14 deletions or insertions, 12 nonsense, nine splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p
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Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
Haematologica, 2010Co-Authors: Jan Rohr, Karin Beutel, Andrea Maul-pavicic, Thomas Vraetz, Jens Thiel, Klaus Warnatz, Ilka Bondzio, Ute Gross-wieltsch, Michael M. Schündeln, Barbara SchützAbstract:Background Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed. Design and Methods We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 . Results All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2 . In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8+ T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal. Conclusions Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.
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linkage of familial hemophagocytic lymphohistiocytosis fhl type 4 to chromosome 6q24 and identification of mutations in syntaxin 11
Human Molecular Genetics, 2005Co-Authors: Udo Zur Stadt, Karin Beutel, Reinhard Schneppenheim, Janinge Henter, Susanne Schmidt, Brigitte Kasper, Sarper A Diler, H Kabisch, Peter NurnbergAbstract:Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10 cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes, we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5 bp deletion. In addition to this family, we found homozygous mutations in STX11 in five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.
Melissa M. Hazen - One of the best experts on this subject based on the ideXlab platform.
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Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis.
Arthritis and rheumatism, 2008Co-Authors: Melissa M. Hazen, Alexei A. Grom, Amy L. Woodward, Inga Hofmann, Barbara A. Degar, Alexandra H. Filipovich, Bryce A. BinstadtAbstract:The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13-4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH-associated genes in patients with systemic JIA have not been reported. We report the case of an 8-year-old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.
