Robinson Research Institute and

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PubMed | University of Ostrava, University of Paris Pantheon Sorbonne, Max Planck Institute for Molecular Genetics, University of Bologna and 3 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Both gain- and loss-of-function mutations have recently implicated HCFC1 in neurodevelopmental disorders. Here, we extend our previous HCFC1 over-expression studies by employing short hairpin RNA to reduce the expression of Hcfc1 in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of HCFC1 in neurological disorders, we report two novel HCFC1 missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported HCFC1 missense variants of unknown pathogenicity, were functionally assessed using multiple cell-based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type HCFC1 caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four HCFC1 variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced ability to localize to the cell nucleus. The other two variants displayed negative effects on the expression of the HCFC1 target gene MMACHC, which is responsible for the metabolism of cobalamin, suggesting that these individuals may also be susceptible to cobalamin deficiency. Together, our work identifies plausible cellular consequences of missense HCFC1 variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain development.


News Article | November 16, 2016
Site: www.sciencedaily.com

Research led by the University of Adelaide has found that women whose babies are conceived in winter are more likely to develop gestational diabetes during pregnancy, increasing a range of risk factors for both child and mother. The study -- investigating more than 60,000 births in South Australia over a five-year period -- is the first population-based study of its kind to confirm a seasonal variation in gestational diabetes. Published in the journal BMJ Diabetes Research & Care, the study was led by the Robinson Research Institute at the University of Adelaide, and involved the University of Groningen in the Netherlands and the Pregnancy Outcome Unit of SA Health. Gestational diabetes mellitus is a serious pregnancy complication characterized by inadequate blood sugar control in pregnancy. Complications of gestational diabetes include excessive birth weight, pre-term birth, low blood sugar (which, in extreme cases, can lead to seizures in the baby), and developing type 2 diabetes later in life. "Our study is the first of its kind to find strong evidence of a relationship between gestational diabetes and the season in which a child is conceived," says lead author Dr Petra Verburg from the University of Groningen, who is currently based at the University of Adelaide's Robinson Research Institute and at the Lyell McEwin Hospital. The study found that: • In the five years from 2007-2011, the incidence of pregnancies affected by gestational diabetes increased, with 4.9% of pregnancies affected in 2007, increasing to 7.2% in 2011 • Women who conceived in winter were more likely to develop gestational diabetes during their pregnancy, with 6.6% of pregnancies from winter conceptions affected • Women who conceived in summer were less likely to develop gestational diabetes, with 5.4% of summer conceptions affected. "The mechanisms that cause gestational diabetes are still not fully understood," Dr Verburg says. "Previous studies have suggested that meteorological factors, physical activity, diet and vitamin D are risk factors for gestational diabetes, all of which are impacted by the winter season. "Not only should our results be confirmed in other populations, future research should also investigate other factors that vary with season," she says. Research leader and senior author Professor Claire Roberts, from the University's Robinson Research Institute, says the results continue to show the broader impacts of the increasing body mass index (BMI) in women of reproductive age. "Elevated BMI and low physical activity are risk factors for gestational diabetes, as well as low socio-economic status. These factors are modifiable, and they represent targets for interventions to prevent the rising tide of gestational diabetes," Professor Roberts says.


News Article | November 15, 2016
Site: www.eurekalert.org

Research led by the University of Adelaide has found that women whose babies are conceived in winter are more likely to develop gestational diabetes during pregnancy, increasing a range of risk factors for both child and mother. The study - investigating more than 60,000 births in South Australia over a five-year period - is the first population-based study of its kind to confirm a seasonal variation in gestational diabetes. Published in the journal BMJ Diabetes Research & Care, the study was led by the Robinson Research Institute at the University of Adelaide, and involved the University of Groningen in the Netherlands and the Pregnancy Outcome Unit of SA Health. Gestational diabetes mellitus is a serious pregnancy complication characterized by inadequate blood sugar control in pregnancy. Complications of gestational diabetes include excessive birth weight, pre-term birth, low blood sugar (which, in extreme cases, can lead to seizures in the baby), and developing type 2 diabetes later in life. "Our study is the first of its kind to find strong evidence of a relationship between gestational diabetes and the season in which a child is conceived," says lead author Dr Petra Verburg from the University of Groningen, who is currently based at the University of Adelaide's Robinson Research Institute and at the Lyell McEwin Hospital. "The mechanisms that cause gestational diabetes are still not fully understood," Dr Verburg says. "Previous studies have suggested that meteorological factors, physical activity, diet and vitamin D are risk factors for gestational diabetes, all of which are impacted by the winter season. "Not only should our results be confirmed in other populations, future research should also investigate other factors that vary with season," she says. Research leader and senior author Professor Claire Roberts, from the University's Robinson Research Institute, says the results continue to show the broader impacts of the increasing body mass index (BMI) in women of reproductive age. "Elevated BMI and low physical activity are risk factors for gestational diabetes, as well as low socio-economic status. These factors are modifiable, and they represent targets for interventions to prevent the rising tide of gestational diabetes," Professor Roberts says. This research has been supported by the National Health and Medical Research Council (NHMRC). Dr Petra Verburg University of Groningen; and Robinson Research Institute The University of Adelaide petra.verburg@adelaide.edu.au


PubMed | University of South Australia, Walter and Eliza Hall Institute of Medical Research, Womens and Childrens Health Research Institute, Robinson Research Institute and and 6 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an 12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

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