Inherited Muscle Disorders

Inherited muscular disorders can manifest at any age, from prenatal life to adulthood. The broad differential diagnosis includes muscular dystrophies, congenital myopathies, disorders of glycogen and lipid metabolism, channelopathies, and mitochondrial disorders. Muscular dystrophies may present at any age, are inherited, and involve progressive degeneration of muscle, which is often replaced by connective tissue. Muscular dystrophies result from defects in the sarcolemmal proteins of muscle, including dystrophin-associated muscle membrane protein complex, muscle intracellular proteins (eg, nuclear envelope proteins), and extracellular matrix proteins (eg, collagen VI).

Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

Co-translational biogenesis of lipid droplet integral membrane proteins

Membrane proteins destined for lipid droplets (LDs), a major intracellular storage site for neutral lipids, are inserted into the endoplasmic reticulum (ER) and then trafficked to LDs where they reside in a hairpin loop conformation. Here, we show that LD membrane proteins can be delivered to the ER either co- or post-translationally and that their membrane-embedded region specifies pathway selection. The co-translational route for LD membrane protein biogenesis is insensitive to a small molecule inhibitor of the Sec61 translocon, Ipomoeassin F, and instead relies on the ER membrane protein complex (EMC) for membrane insertion. This route may even result in a transient exposure of the short N-termini of some LD membrane proteins to the ER lumen, followed by putative topological rearrangements that would enable their transmembrane segment to form a hairpin loop and N-termini to face the cytosol. Our study reveals an unexpected complexity to LD membrane protein biogenesis and identifies a role for the EMC during their co-translational insertion into the ER.

Co-translational biogenesis of lipid droplet integral membrane proteins

Membrane proteins destined for lipid droplets (LDs), a major intracellular storage site for neutral lipids, are inserted into the endoplasmic reticulum (ER) and then trafficked to LDs where they reside in a hairpin loop conformation. Here, we show that LD membrane proteins can be delivered to the ER either co- or post-translationally and that their membrane-embedded region specifies pathway selection. The co-translational route for LD membrane protein biogenesis is insensitive to a small molecule inhibitor of the Sec61 translocon, Ipomoeassin F, and instead relies on the ER membrane protein complex (EMC) for membrane insertion. Strikingly, this route can also result in a transient exposure of the short N-termini of LD membrane proteins to the ER lumen, followed by topological rearrangements that enable their transmembrane segment to form a hairpin loop and N-termini to face the cytosol. Our study reveals an unexpected complexity to LD membrane protein biogenesis and identifies a role for the EMC during their co-translational insertion into the ER.

Molecular Detection of Chlamydia Trachomatis Associated with Ocular Infection among Children in Gadarif State-Sudan

Background: Trachoma is the leading cause of infectious blindness worldwide. Trachoma is endemic in parts of Africa, the middle east, and India. The disease is particularly problematic in particular Ethiopia and Sudan regions. Objectives :To detect Chlamydia trachomatis among active trachoma children using molecular technique in -Gadarif State- Sudan Methodology: A population-based prevalence study was conducted during the period from Nov 2016 to Nov 2017. A total of 318 children were surveyed; their ages range between 1 to 9 years old. The children's eyes were examined for trachoma follicles and trachoma inflammatory intense (TF, and TI). Samples were collected on Swabs from children clinically diagnosed as active trachoma for the DNA analysis, and collection was done from the tarsal conjunctival surface with a dacron polyester swab and with UTM media, DNA was extracted and amplified by molecular technique with Touchdown protocol and primers for C. trachomatis outer membrane protein complex B ( omcB). Data was collected by direct interviewing questionnaire; ethical approval was obtained from Ethical Research Committee -Al Neelain University Result: Out of the total 318 children, 83(26.1%) children were positive for the C trachomatis omc B gene; Sequencing was performed for both strands of omc B genes, found that the circulating strain in Sudan Gdarif state is similar genetically to the classical one registered in NCBI Conclusion: Chlamydia trachomatis is one of the causative agents of trachoma in Sudan, the circulating strain in Sudan Gdarif state is similar genetically to the classical one registered in NCBI Keywords: Chlamydia trachomatis- omc B genes- PCR- Trachoma- Sudan

Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

Tocopherol controls D1 amino acid oxidation by oxygen radicals in Photosystem II

Photosystem II (PSII) is an intrinsic membrane protein complex that functions as a light-driven water:plastoquinone oxidoreductase in oxygenic photosynthesis. Electron transport in PSII is associated with formation of reactive oxygen species (ROS) responsible for oxidative modifications of PSII proteins. In this study, oxidative modifications of the D1 and D2 proteins by the superoxide anion (O2•−) and the hydroxyl (HO•) radicals were studied in WT and a tocopherol cyclase (vte1) mutant, which is deficient in the lipid-soluble antioxidant α-tocopherol. In the absence of this antioxidant, high-resolution tandem mass spectrometry was used to identify oxidation of D1:130E to hydroxyglutamic acid by O2•− at the PheoD1 site. Additionally, D1:246Y was modified to either tyrosine hydroperoxide or dihydroxyphenylalanine by O2•− and HO•, respectively, in the vicinity of the nonheme iron. We propose that α-tocopherol is localized near PheoD1 and the nonheme iron, with its chromanol head exposed to the lipid–water interface. This helps to prevent oxidative modification of the amino acid’s hydrogen that is bonded to PheoD1 and the nonheme iron (via bicarbonate), and thus protects electron transport in PSII from ROS damage.