Tuesday, November 22, 2016

Review of involvement in disease of human orthologs of the Drosophila gene crumbs

Slavotinek AM. The Family of Crumbs Genes and Human Disease. Mol Syndromol. 2016 Oct;7(5):274-281. PMID: 27867342.

From the abstract: "The family of vertebrate Crumbs proteins, homologous to Drosophila Crumbs (Crb), share large extracellular domains with epidermal growth factor-like repeats and laminin-globular domains, a single transmembrane domain, and a short intracellular C-terminus containing a single membrane proximal 4.1/ezrin/radixin/moesin-binding domain and PSD-95/Discs large/ZO-1-binding motifs. There are 3 Crb genes in humans ... Bilallelic loss-of-function mutations in CRB1 cause visual impairment, with Leber's congenital amaurosis and retinitis pigmentosa, whereas CRB2 mutations are associated with raised maternal serum and amniotic fluid alpha feto-protein levels, ventriculomegaly/hydrocephalus, and renal disease, ranging from focal segmental glomerulosclerosis to congenital Finnish nephrosis. ... In this review, we summarize the phenotypic findings associated with deleterious sequence variants in CRB1 and CRB2. We discuss the mutational spectrum, animal models of loss of function for both genes and speculate on the likely mechanisms of disease."

Thursday, October 27, 2016

Do p53 mutations result in 'transposon-opathies'?

The interesting argument regarding p53, transposons, and cancer that is presented in this review draws in part from studies done in flies.

Wylie A, Jones AE, Abrams JM. p53 in the game of transposons. Bioessays. 2016 Nov;38(11):1111-1116. PMID: 27644006.

From the abstract: "Throughout the animal kingdom, p53 genes function to restrain mobile elements and recent observations indicate that transposons become derepressed in human cancers. ..."

Wednesday, October 26, 2016

Review of animal models of SMA

Edens BM, Ajroud-Driss S, Ma L, Ma YC. Molecular mechanisms and animal models of spinal muscular atrophy. Biochim Biophys Acta. 2015 Apr;1852(4):685-92. PMID: 25088406.

Fly, mouse, and human cell models of Duchenne muscular dystrophy used to evaluate exon skipping as a potential therapeutic strategy

Gao QQ, Wyatt E, Goldstein JA, LoPresti P, Castillo LM, Gazda A, Petrossian N, Earley JU, Hadhazy M, Barefield DY, Demonbreun AR, Bönnemann C, Wolf M, McNally EM. Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. J Clin Invest. 2015 Nov 2;125(11):4186-95. PMID: 26457733; PMCID: PMC4639981.

From the abstract: "Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. ... Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. ... We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations."

Fly model of Alzheimer's disease tested with potentially bioactive viridins extracted from endolichenic fungi

Zhao Q, Chen GD, Feng XL, Yu Y, He RR, Li XX, Huang Y, Zhou WX, Guo LD, Zheng YZ, Yao XS, Gao H. Nodulisporiviridins A-H, Bioactive Viridins from Nodulisporium sp. J Nat Prod. 2015 Jun 26;78(6):1221-30. PMID: 25978520.

From the abstract: "Eight new viridins, nodulisporiviridins A-H (1-8), were isolated from the extract of an endolichenic fungal strain Nodulisporium sp. (No. 65-17-2-1) that was fermented with potato-dextrose broth. ... The short-term memory assay on an Aβ transgenic drosophila model of Alzheimer's disease showed that all eight compounds improved the short-term memory capacity, with potencies close to that of the positive control (memantine)."

Fly eye study related to Alzheimer's disease

Cutler T, Sarkar A, Moran M, Steffensmeier A, Puli OR, Mancini G, Tare M, Gogia N, Singh A. Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease. PLoS One. 2015 Sep 14;10(9):e0137691. PMID: 26367392; PMCID: PMC4569556.

Characterization of sleep in a fly model of epilepsy

Petruccelli E, Lansdon P, Kitamoto T. Exaggerated Nighttime Sleep and Defective Sleep Homeostasis in a Drosophila Knock-In Model of Human Epilepsy. PLoS One. 2015 Sep 11;10(9):e0137758. PMID: 26361221; PMCID: PMC4567262.

From the abstract: "Despite an established link between epilepsy and sleep behavior, it remains unclear how specific epileptogenic mutations affect sleep and subsequently influence seizure susceptibility. ... Here, we show that at room temperature the GEFS+ mutation dominantly modifies sleep, with mutants exhibiting rapid sleep onset at dusk and increased nighttime sleep as compared to controls.  ... Additionally, analyses under other light conditions suggested that the GEFS+ mutation led to reduced buffering of behavioral responses to light on and off stimuli, which contributed to characteristic GEFS+ sleep phenotypes. ... Our study has revealed the sleep architecture of a Drosophila VGSC mutant that harbors a human GEFS+ mutation, and provided unique insight into the relationship between sleep and epilepsy."