RESUMO
OBJECTIVES: Asian men who have sex with men (MSM) who have recently arrived in Australia are an emergent risk group for HIV; however, little is known about how they compare to Australian MSM diagnosed with HIV. This study compared the characteristics of these two groups. METHODS: A retrospective, cross-sectional study of MSM diagnosed with HIV between January 2014 and October 2017 in Melbourne and Sydney public sexual health clinics. Asian MSM were those who had arrived in Australia within 4 years of diagnosis. RESULTS: Among 111 Asian men, 75% spoke a language other than English, 88% did not have Medicare and 61% were international students. Compared with Australian men (n=209), Asian men reported fewer male sexual partners within 12 months (median 4 versus 10, p<0.001), were less likely to have tested for HIV previously (71% versus 89%, p<0.001) and had a lower median CD4 count (326 versus 520, p<0.001). Among Asian men, HIV subtype CRF01-AE was more common (55% versus 16%, p<0.001) and subtype B less common (29% versus 73%, p<0.001). CONCLUSIONS: Asian MSM diagnosed with HIV reported lower risk and had more advanced HIV. Implications for public health: HIV testing and preventative interventions supporting international students are required.
Assuntos
Povo Asiático/estatística & dados numéricos , Emigrantes e Imigrantes/estatística & dados numéricos , Infecções por HIV/diagnóstico , Homossexualidade Masculina/etnologia , Comportamento Sexual/etnologia , Infecções Sexualmente Transmissíveis/etnologia , Adolescente , Adulto , Povo Asiático/psicologia , Austrália/epidemiologia , Estudos Transversais , Infecções por HIV/etnologia , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estudos Retrospectivos , Assunção de Riscos , Parceiros Sexuais , Adulto JovemRESUMO
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.
Assuntos
Transporte Biológico/genética , Cílios/metabolismo , Nefropatias/genética , Mutação , Animais , Ataxia Cerebelar/genética , Criança , Estudos de Coortes , Progressão da Doença , Exoma , Humanos , Nefropatias/patologia , Masculino , Camundongos , Retinose Pigmentar/genéticaRESUMO
IFT80, a protein component of intraflagellar transport (IFT) complex B, is required for the formation, maintenance and functionality of cilia. Mutations in IFT80 cause Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III. Both diseases are autosomal recessive chondrodysplasias and share clinical and radiological similarities, including shortening of the long bones and constriction of the thoracic cage. A murine Ift80 gene-trap line was used to investigate the role of Ift80 during development. The homozygote appears hypomorphic rather than a true null due to low level wild-type transcript production by alternative splicing around the gene-trap cassette. Hypomorphic levels of Ift80 result in embryonic lethality highlighting a key role for Ift80 in development. In rare cases, gene-trap homozygotes survive to postnatal stages and phenocopy both JATD and SRP type III by exhibiting growth retardation, shortening of the long bones, constriction of the ribcage and polydactyly. Mouse embryonic fibroblasts made from this line showed a significant reduction in hedgehog pathway activation in response to Hedgehog analog treatment. This defective signalling was not accompanied by the loss or malformation of cilia as seen in some knockout models of other IFT component genes. Phenotypes indicative of defects in cilia structure or function such as situs inversus, cystic renal disease and retinal degeneration were not observed in this line. These data suggest that there is an absolute requirement for Ift80 in hedgehog signalling, but low level expression permits ciliogenesis indicating separate but linked roles for this protein in formation and function.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas Hedgehog/metabolismo , Síndrome de Costela Curta e Polidactilia/metabolismo , Transdução de Sinais , Animais , Proteínas de Transporte/genética , Células Cultivadas , Cílios , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas Hedgehog/genética , Humanos , Camundongos , Camundongos Mutantes , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Costela Curta e Polidactilia/patologia , Transcrição GênicaRESUMO
Meckel-Gruber syndrome (MKS) is a genetically heterogeneous, neonatally lethal malformation and the most common form of syndromic neural tube defect (NTD). To date, several MKS-associated genes have been identified whose protein products affect ciliary function. Here we show that mutations in MKS1, MKS3 and CEP290 (also known as NPHP6) either can cause Bardet-Biedl syndrome (BBS) or may have a potential epistatic effect on mutations in known BBS-associated loci. Five of six families with both MKS1 and BBS mutations manifested seizures, a feature that is not a typical component of either syndrome. Functional studies in zebrafish showed that mks1 is necessary for gastrulation movements and that it interacts genetically with known bbs genes. Similarly, we found two families with missense or splice mutations in MKS3, in one of which the affected individual also bears a homozygous nonsense mutation in CEP290 that is likely to truncate the C terminus of the protein. These data extend the genetic stratification of ciliopathies and suggest that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum.
Assuntos
Antígenos de Neoplasias/genética , Síndrome de Bardet-Biedl/genética , Encefalocele/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas de Neoplasias/genética , Proteínas/genética , Peixe-Zebra/crescimento & desenvolvimento , Adulto , Processamento Alternativo , Sequência de Aminoácidos , Animais , Síndrome de Bardet-Biedl/patologia , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Feminino , Gastrulação , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Gravidez , Homologia de Sequência de Aminoácidos , Síndrome , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia.