Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This `experiment of nature` indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.

ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q(10) deficiency

Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphomositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.

Conflicting structural and geochronological data from the Ibituruna quartz-syenite (SE Brazil): Effect of protracted ""hot"" orogeny and slow cooling rate?

The Ibituruna quartz-syenite was emplaced as a sill in the Ribeira-Aracuai Neoproterozoic belt (Southeastern Brazil) during the last stages of the Gondwana supercontinent amalgamation. We have measured the Anisotropy of Magnetic Susceptibility (AMS) in samples from the Ibituruna sill to unravel its magnetic fabric that is regarded as a proxy for its magmatic fabric. A large magnetic anisotropy, dominantly due to magnetite, and a consistent magnetic fabric have been determined over the entire Ibituruna massif. The magmatic foliation and lineation are strikingly parallel to the solid-state mylonitic foliation and lineation measured in the country-rock. Altogether, these observations suggest that the Ibituruna sill was emplaced during the high temperature (similar to 750 degrees C) regional deformation and was deformed before full solidification coherently with its country-rock. Unexpectedly, geochronological data suggest a rather different conclusion. LA-ICP-MS and SHRIMP ages of zircons from the Ibituruna quartz-syenite are in the range 530-535 Ma and LA-ICP-MS ages of zircons and monazites from synkinematic leucocratic veins in the country-rocks suggest a crystallization at similar to 570-580 Ma, i.e., an HT deformation >35My older than the emplacement of the Ibituruna quartz-syenite. Conclusions from the structural and the geochronological studies are therefore conflicting. A possible explanation arises from (40)Ar-(39)Ar thermochronology. We have dated amphiboles from the quartz-syenite, and amphiboles and biotites from the country-rock. Together with the ages of monazites and zircons in the country-rock, (40)Ar-(39)Ar mineral ages suggest a very low cooling rate: <3 degrees C/My between 570 and similar to 500 Ma and similar to 5 degrees C/My between 500 and 460 Ma. Assuming a protracted regional deformation consistent over tens of My, under such stable thermal conditions the fabric and microstructure of deformed rocks may remain almost unchanged even if they underwent and recorded strain pulses separated by long periods of time. This may be a characteristic of slow cooling ""hot orogens"" that rocks deformed at significantly different periods during the orogeny, but under roughly unchanged temperature conditions, may display almost indiscernible microstructure and fabric. (C) 2009 Elsevier B.V. All rights reserved.