CRISTINA MIUKI ABE JACOB
Projetos de Pesquisa
Unidades Organizacionais
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina - Líder
4 resultados
Resultados de Busca
Agora exibindo 1 - 4 de 4
conferenceObject The Extended Clinical Phenotype of 36 Patients with Chronic Mucocutaneous Candidiasis Due to Gain-of-Function Mutations in STAT1(2014) FREDE, N.; DEPNER, M.; RAABE, J.; DOFFINGER, R.; GKRANIA-KLOTSAS, E.; KUMARARATNE, D.; ATKINSON, T. P.; SCHROEDER, H. W.; NIEHUES, T.; DUECKERS, G.; PUCK, J.; EISENSTEIN, E. M.; STRAY-PEDERSEN, A.; BAUMANN, U.; SCHMIDT, R. E.; FRANCO, J. L.; ORREGO, J. C.; BEN-SHOSHAN, M.; MCCUSKER, C.; JACOB, C. M.; CARNEIRO-SAMPAIO, M.; DEVLIN, L. A.; EDGAR, J. D.; HENDERSON, P.; DYRSO, T.; SENEVIRATNE, S. L.; WANDERS, J.; STAUSS, H.; MEYTS, I.; MOENS, L.; JESENAK, M.; GRIMBACHER, B.- The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1(2016) DEPNER, Mark; FUCHS, Sebastian; RAABE, Jan; FREDE, Natalie; GLOCKER, Cristina; DOFFINGER, Rainer; GKRANIA-KLOTSAS, Effrossyni; KUMARARATNE, Dinakantha; ATKINSON, T. Prescott; SCHROEDER JR., Harry W.; NIEHUES, Tim; DUECKERS, Gregor; STRAY-PEDERSEN, Asbjorg; BAUMANN, Ulrich; SCHMIDT, Reinhold; FRANCO, Jose L.; ORREGO, Julio; BEN-SHOSHAN, Moshe; MCCUSKER, Christine; JACOB, Cristina Miuki Abe; CARNEIRO-SAMPAIO, Magda; DEVLIN, Lisa A.; EDGAR, J. David M.; HENDERSON, Paul; RUSSELL, Richard K.; SKYTTE, Anne-Bine; SENEVIRATNE, Suranjith L.; WANDERS, Jennifer; STAUSS, Hans; MEYTS, Isabelle; MOENS, Leen; JESENAK, Milos; KOBBE, Robin; BORTE, Stephan; BORTE, Michael; WRIGHT, Dowain A.; HAGIN, David; TORGERSON, Troy R.; GRIMBACHER, BodoPurpose Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. Methods STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-alpha, IFN-gamma or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. Results Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. Conclusion STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
conferenceObject MUTATION SCREENING IN STAT1, CARD9 AND PKC-DELTA IN PATIENTS WITH CHRONIC MUCOCUTANEOUS CANDIDIASIS(2012) DEPNER, M.; VEERDONK, F. van de; WANDERS, J.; STAUSS, H.; RAABE, J.; ATKINSON, T. P.; SCHROEDER JR., H. W.; NIEHUES, T.; DUECKERS, G.; PUCK, J.; STRAY-PEDERSEN, A.; BAUMANN, U.; SCHMIDT, R.; FRANCO, J. L.; ORREGO, J.; BEN-SHOSHAN, M.; MCCUSKER, C.; JACOB, C. M. A.; CARNEIRO-SAMPAIO, M.; DEVLIN, L. A.; EDGAR, J. D.; GKRANIA-KLOTSAS, E.; KUMARARATNE, D.; DOFFINGER, R.; HENDERSON, P.; RUSSELL, R. K.; DYRSO, T.; SENEVIRATNE, S. L.; MATTHIJS, G.; ABINUN, M.; GENNERY, A.; JOHNSON, M.; MEER, J. W. M. van der; NETEA, M. G.; LILIC, D.; GRIMBACHER, B.conferenceObject Gain-of-function mutations in STAT1: A new molecular cause for patients with chronic mucocutaneous candidiasis(2012) DEPNER, M.; WANDERS, J.; STAUSS, H.; JANSSON, A.; DUECKERS, G.; NIEHUES, T.; BAUMANN, U.; PEDERSEN, A. Stray; KILIC, S. S.; ATKINSON, T. P.; PUCK, J. M.; FRANCO, J. L.; DEVLIN, L.; JENSEN, T. D.; HENDERSON, P.; MATTHIJS, G.; SHOSHAN, M. Ben; MCCUSKER, C.; JACOB, C. M.; GRIMBACHER, B.Background: Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of skin, nails or mucosa with candida species. Most of the cases are sporadic; however, both autosomal dominant and autosomal recessive inheritance has been reported. Recent research suggests that autosomal dominant CMC may be due to heterozygous gain-of-function mutations in the signalling protein STAT1. Methods: We studied twelve unrelated families with autosomal dominant CMC and ten sporadic patients. We sequenced the genomic DNA of affected individuals, searching for heterozygous mutations in the 15 exons covering the coiled-coil and DNA-binding domain of STAT1. Results: After performing Sanger sequencing on all patients, we identified five different missense mutations in the coiled-coil domain of STAT1 in eight of the twelve CMC families. We then focused on sequencing the sporadic cases. In three of ten sporadic CMC patients we identified heterozygous missense mutation in the DNA-binding domain of STAT1. Conclusion: Missense mutations in the coiled-coil and DNA-binding domain of STAT1 may be the cause for sporadic and autosomal dominant CMC. Thus, STAT1 has to be taken into account when diagnosing this condition. The mutations we report are gain-of-function mutations. Interestingly, loss-of-function mutations in STAT1 lead to the susceptibility to mycobacterial and viral diseases.