1. Ferron L, Nieto-Rostro M, Cassidy JS, Dolphin AC. {{Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density}}. {Nat Commun};2014;5:3628.
Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.
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2. Suren P, Gunnes N, Roth C, Bresnahan M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T, Schjolberg S, Susser E, Oyen AS, Smith GD, Stoltenberg C. {{Parental Obesity and Risk of Autism Spectrum Disorder}}. {Pediatrics};2014 (Apr 7)
OBJECTIVES: The objective of the study was to investigate the associations among maternal prepregnancy BMI, paternal BMI, and the risk of autism spectrum disorders (ASDs) in children. METHODS: The study sample of 92 909 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study. The age range was 4.0 through 13.1 (mean 7.4) years. Relative risks of ASDs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models. RESULTS: At the end of follow-up on December 31, 2012, 419 children in the study sample had been diagnosed with ASDs: 162 with autistic disorder, 103 with Asperger disorder, and 154 with pervasive developmental disorder not otherwise specified. Maternal obesity (BMI >/=30) was only weakly associated with ASD risk, whereas paternal obesity was associated with an increased risk of autistic disorder and Asperger disorder. The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41 603) in children of fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07-2.82). For Asperger disorder, analyses were limited to children aged >/=7 years (n = 50 116). The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18% (42 of 22 736) in children of normal-weight fathers, and the adjusted OR was 2.01 (95% CI: 1.13-3.57). No associations were found for pervasive developmental disorder not otherwise specified. CONCLUSIONS: Paternal obesity is an independent risk factor for ASDs in children. The associations should be investigated further in genetic and epigenetic studies.
