MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency

The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication

A recurrent gain-of-function mutation in CLCN6, encoding the ClC-6 Cl-/H+-exchanger, causes early-onset neurodegeneration

Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl(-)/H(+) exchangers function as electric shunts for proton pumping and in luminal Cl(-) accumulation. We now report three unrelated children with severe neurodegenerative disease, who carry the same de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6, encoding the late endosomal Cl(-)/H(+)-exchanger ClC-6. Whereas Clcn6(-/-) mice have only mild neuronal lysosomal storage abnormalities, the affected individuals displayed severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. The p.Tyr553Cys amino acid substitution strongly slowed ClC-6 gating and increased current amplitudes, particularly at the acidic pH of late endosomes. Transfection of ClC-6(Tyr553Cys), but not ClC-6(WT), generated giant LAMP1-positive vacuoles that were poorly acidified. Their generation strictly required ClC-6 ion transport, as shown by transport-deficient double mutants, and depended on Cl(-)/H(+) exchange, as revealed by combination with the uncoupling p.Glu200Ala substitution. Transfection of either ClC-6(Tyr553Cys/Glu200Ala) or ClC-6(Glu200Ala) generated slightly enlarged vesicles, suggesting that p.Glu200Ala, previously associated with infantile spasms and microcephaly, is also pathogenic. Bafilomycin treatment abrogated vacuole generation, indicating that H(+)-driven Cl(-) accumulation osmotically drives vesicle enlargement. Our work establishes mutations in CLCN6 associated with neurological diseases, whose spectrum of clinical features depends on the differential impact of the allele on ClC-6 function

Degradation of o 12xylene by Pseudomonas stutzeri OX1 (Pseudomonas sp. OX1)

Interest in the microbial degradation of methylbenzenes arose in the early 1970s, when both toxicological and ecological data started to alert people about their wide distribution in the environment and their effects on living organisms. Most of the early studies on bacterial methylbenzene catabolism focused on bacteria belonging to the genus Pseudomonas, which proved to be endowed with a formidable metabolic versatility. Several Pseudomonas strains isolated then for their ability to degrade toluene, mand p-xylene, and 1,2,4-trimethylbenzene, later become the archetypes for the studies on the biochemistry, genetics and regulation of methylbenzene degradation (see also volume 2, Chapter 18 and volume 4, Chapter 7)

Certified Reference Material IAEA-446 for radionuclides in Baltic Sea seaweed

Proceedings of the 19th International Conference on Radionuclide Metrology and its Applications 17–21 June 2013, Antwerp, Belgium.-- et al.A Certified Reference Material (CRM) for radionuclides in seaweed (Fucus vesiculosus) from the Baltic Sea (IAEA-446) is described and the results of the certification process are presented. The 40K, 137Cs, 234U and 239+240Pu radionuclides were certified for this material, and information values for 12 other radionuclides (90Sr, 99Tc, 210Pb (210Po), 226Ra, 228Ra, 228Th, 230Th, 232Th, 235U, 238U, 239Pu and 240Pu) are presented. The CRM can be used for Quality Assurance/Quality Control of analysis of radionuclides in seaweed and other biota samples, as well as for development and validation of analytical methods, and for training purposes.Peer Reviewe