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Boyce K.J.,University of Melbourne | McLauchlan A.,South Australian Clinical Genetics Service | Schreider L.,University of Melbourne | Andrianopoulos A.,University of Melbourne
PLoS Pathogens | Year: 2015

During infection, pathogens must utilise the available nutrient sources in order to grow while simultaneously evading or tolerating the host’s defence systems. Amino acids are an important nutritional source for pathogenic fungi and can be assimilated from host proteins to provide both carbon and nitrogen. The hpdA gene of the dimorphic fungus Penicillium marneffei, which encodes an enzyme which catalyses the second step of tyrosine catabolism, was identified as up-regulated in pathogenic yeast cells. As well as enabling the fungus to acquire carbon and nitrogen, tyrosine is also a precursor in the formation of two types of protective melanin; DOPA melanin and pyomelanin. Chemical inhibition of HpdA in P. marneffei inhibits ex vivo yeast cell production suggesting that tyrosine is a key nutrient source during infectious growth. The genes required for tyrosine catabolism, including hpdA, are located in a gene cluster and the expression of these genes is induced in the presence of tyrosine. A gene (hmgR) encoding a Zn(II)2-Cys6 binuclear cluster transcription factor is present within the cluster and is required for tyrosine induced expression and repression in the presence of a preferred nitrogen source. AreA, the GATA-type transcription factor which regulates the global response to limiting nitrogen conditions negatively regulates expression of cluster genes in the absence of tyrosine and is required for nitrogen metabolite repression. Deletion of the tyrosine catabolic genes in the cluster affects growth on tyrosine as either a nitrogen or carbon source and affects pyomelanin, but not DOPA melanin, production. In contrast to other genes of the tyrosine catabolic cluster, deletion of hpdA results in no growth within macrophages. This suggests that the ability to catabolise tyrosine is not required for macrophage infection and that HpdA has an additional novel role to that of tyrosine catabolism and pyomelanin production during growth in host cells. © 2015 Boyce et al.

O'Callaghan M.E.,University of Adelaide | MacLennan A.H.,University of Adelaide | McMichael G.L.,University of Adelaide | Haan E.A.,South Australian Clinical Genetics Service | And 2 more authors.
Pediatric Research | Year: 2013

Background:The aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at <37 completed weeks of gestation) and synthesize currently available evidence using meta-analysis.Methods:Spontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates.Results:A cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4).Conclusion:Replication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation. Copyright © 2013 International Pediatric Research Foundation, Inc.

Hoischen A.,Radboud University Nijmegen | Van Bon B.W.M.,Radboud University Nijmegen | Gilissen C.,Radboud University Nijmegen | Arts P.,Radboud University Nijmegen | And 20 more authors.
Nature Genetics | Year: 2010

Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect. © 2010 Nature America, Inc. All rights reserved.

Gai D.,Royal Melbourne Hospital | Haan E.,South Australian Clinical Genetics Service | Haan E.,University of Adelaide | Scholar M.,Flinders Medical Center | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

AKT3 (v-akt murine thymoma viral oncogene homolog 3) is located at chromosome 1q44 and encodes a 479 amino acid protein, a member of the protein kinase B (PKB) family. This gene is frequently involved in 1q44 deletion syndrome in patients with microcephaly, intellectual disability, and dysmorphic features. Phenotype and genotype studies of patients with 1q44 deletion syndrome have suggested that deletion of the AKT3 gene is responsible for the microcephaly in these patients. However, the phenotype of pure AKT3 deletion has not been studied. We report on a 1q44 deletion involving only AKT3 in a boy and his father. The boy has microcephaly, hypotonia, feeding difficulties, developmental delay, and minor dysmorphic features. His father does not have microcephaly and is of normal intelligence. We also analyzed the available information on the phenotypes of 13 individuals carrying a pure AKT3 gene deletion identified through literature review and database search. To our knowledge, this is the first report of a paternally inherited pure AKT3 deletion with full clinical description. This is also the first report to suggest that (1) AKT3 deletion is associated with microcephaly and intellectual disability with incomplete penetrance; (2) a pure AKT3 deletion is likely to be inherited in contrast to the larger 1q44 deletions, which are mostly de novo and (3) there seems to be no consistent or characteristic dysmorphism associated with pure AKT3 deletion. © 2014 Wiley Periodicals, Inc.

Heron S.E.,University of South Australia | Grinton B.E.,University of Melbourne | Afawi Z.,Tel Aviv University | Zuberi S.M.,Paediatric Neurosciences Research Group | And 19 more authors.
American Journal of Human Genetics | Year: 2012

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia). © 2012 The American Society of Human Genetics.

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