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German Research Foundation (DFG) Telethon-Italy Associazione ONLUS Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. the NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. in a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype-phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects. Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, D-8520 Erlangen, Germany Univ Hosp Munster, Dept Human Genet, Munster, Germany Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada Universidade Federal de São Paulo, São Paulo, Brazil Royal Manchester Childrens Hosp, Manchester M27 1HA, Lancs, England Univ Cattolica, Inst Med Genet, Rome, Italy Univ Kentucky, Coll Med, Div Cardiol, Dept Pediat, Lexington, KY USA Ist Super Sanita, Dipartimento Biol Cellulare & Neurosci, I-00161 Rome, Italy Royal Childrens Hosp, Genet Hlth Queensland, Herston, Qld, Australia Max Planck Inst Mol Genet, Berlin, Germany Univ Hosp Rostock, Med Genet Unit, Dept Pediat, Rostock, Germany Univ Hosp Dusseldorf, Dept Human Genet, Dusseldorf, Germany Univ Hosp Munster, Dept Pediat Cardiol, Munster, Germany Univ Hosp Essen, Dept Human Genet, Essen, Germany Wroclaw Med Univ, Dept Maxilla Facial Surg, Wroclaw, Poland Wroclaw Med Univ, Dept Genet, Wroclaw, Poland Mater Pathol Serv, Brisbane, Qld, Australia Univ Hosp Charite, Dept Med Genet, Berlin, Germany Universidade Federal de São Paulo, São Paulo, Brazil German Research Foundation (DFG): Ze 524/4-1 Telethon-Italy: GGP07115 Web of Science

Made available in DSpace on 2015-10-21T13:11:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-15. Added 1 bitstream(s) on 2015-10-22T09:52:15Z : No. of bitstreams: 1 WOS000349703400001.pdf: 1826227 bytes, checksum: df2e17fdccd3931a1583bd53d960e181 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Background: Several species of protozoa cause acute or chronic gastroenteritis in humans, worldwide. The burden of disease is particularly high among children living in developing areas of the world, where transmission is favored by lower hygienic standards and scarce availability of safe water. However, asymptomatic infection and polyparasitism are also commonly observed in poor settings. Here, we investigated the prevalence of intestinal protozoa in two small fishing villages, Porto Said (PS) and Santa Maria da Serra (SM), situated along the river Tiete in the State of Sao Paolo, Brazil. The villages lack basic public infrastructure and services, such as roads, public water supply, electricity and public health services.Methods: Multiple fecal samples were collected from 88 individuals in PS and from 38 individuals in SM, who were asymptomatic at the time of sampling and had no recent history of diarrheal disease. To gain insights into potential transmission routes, 49 dog fecal samples (38 from PS and 11 from SM) and 28 river water samples were also collected. All samples were tested by microscopy and PCR was used to genotype Giardia duodenalis, Blastocystis sp., Dientamoeba fragilis and Cryptosporidium spp.Results: By molecular methods, the most common human parasite was Blastocystis sp. (prevalence, 45% in PS and 71% in SM), followed by D. fragilis (13.6% in PS, and 18.4% in SM) and G. duodenalis (18.2% in PS and 7.9% in SM); Cryptosporidium spp. were not detected. Sequence analysis revealed large genetic variation among Blastocystis samples, with subtypes (STs) 1 and 3 being predominant, and with the notable absence of ST4. Among G. duodenalis samples, assemblages A and B were detected in humans, whereas assemblages A, C and D were found in dogs. Finally, all D. fragilis samples from humans were genotype 1. A single dog was found infected with Cryptosporidium canis. River water samples were negative for the investigated parasites.Conclusions: This study showed a high carriage of intestinal parasites in asymptomatic individuals from two poor Brazilian villages, and highlighted a large genetic variability of Blastocystis spp. and G. duodenalis. Sao Paulo State Univ, UNESP, Inst Biosci, Dept Parasitol, BR-18618970 Botucatu, SP, Brazil Univ Estadual Campinas, Inst Biol, Dept Anim Biol, BR-13083970 Campinas, SP, Brazil Ist Super Sanita, Dept Infect Parasit &Immunomediated Dis, I-00161 Rome, Italy Sao Paulo State Univ, UNESP, Inst Biosci, Dept Parasitol, BR-18618970 Botucatu, SP, Brazil FAPESP: 2011/52100-3