Maternal uniparental isodisomy and heterodisomy on chromosome 6 encompassing a CUL7 gene mutation causing 3M syndrome.

We report a case of segmental uniparental maternal hetero- and isodisomy involving the whole of chromosome 6 (mat-hUPD6 and mat-iUPD6) and a cullin 7 (CUL7) gene mutation in a Japanese patient with 3M syndrome. 3M syndrome is a rare autosomal recessive disorder characterized by severe pre- and postnatal growth retardation that was recently reported to involve mutations in the CUL7 or obscurin-like 1 (OBSL1) genes. We encountered a patient with severe growth retardation, an inverted triangular gloomy face, an inverted triangle-shaped head, slender long bones, inguinal hernia, hydrocele testis, mild ventricular enlargement, and mild mental retardation. Sequence analysis of the CUL7 gene of the patient revealed a homozygous missense mutation, c.2975G>C. Genotype analysis using a single nucleotide polymorphism array revealed two mat-hUPD and two mat-iUPD regions involving the whole of chromosome 6 and encompassing CUL7. 3M syndrome caused by complete paternal iUPD of chromosome 6 involving a CUL7 mutation has been reported, but there have been no reports describing 3M syndrome with maternal UPD of chromosome 6. Our results represent a combination of iUPDs and hUPDs from maternal chromosome 6 involving a CUL7 mutation causing 3M syndrome.

Non-hotspot-related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions.

BACKGROUND: Sotos syndrome (SoS) is a disorder characterised by excessive growth, typical craniofacial features, and developmental retardation. It is caused by haploinsuffiency of NSD1 at 5q35. There is a 3.0 kb recombination hotspot in which the breakpoints of around 80% of SoS patients with a common deletion can be mapped. OBJECTIVE: To identify deletion breakpoints located outside the SoS recombination hotspot. METHODS: A screening system for the directly orientated segments of the SoS LCRs was developed for 10 SoS patients with a common deletion who were negative for the SoS hotspot. Deletion-junction fragments were analysed for DNA duplex stability and their relation to scaffold/matrix attachment regions (S/MARs). These features were compared with the SoS hotspot and recombination hotspots of other genomic disorders. RESULTS: The breakpoint was mapped in four SoS patients, two with a deletion in the maternally derived chromosome. These breakpoint regions were located approximately 2.5 kb, approximately 9.6 kb, approximately 27.2, and approximately 27.7 kb telomeric to the SoS hotspot and were confined to 164 bp, 46 bp, 256 bp, and 124 bp, respectively. Two of the regions were mapped within Alu elements. All crossover events were found to have occurred within or adjacent to a highly destabilised DNA duplex with a high S/MAR probability. In contrast, the SoS hotspot and other genomic disorders' recombination hotspots were mapped to stabilised DNA helix regions, flanked by destabilised regions with high probability of containing S/MAR elements. CONCLUSIONS: The data suggest that a specific chromatin structure may increase susceptibility for recurrent crossover events and thus predispose to recombination hotspots in genomic disorders.

Accumulation of 14 alpha-methylergosta-8,24(28)-dien-3 beta,6 alpha-diol in 14 alpha-demethylation mutants of Candida albicans: genetic evidence for the involvement of 5-desaturase.

14 alpha-Demethylation mutants of the fungus Candida albicans have been shown to accumulate 14 alpha-methylergosta-8,24(28)-dien-3 beta,6 alpha-diol. A derivative from one of these mutants (KD4900) that does not form this 6 alpha-hydroxylated sterol but is still defective in 14 alpha-demethylation (KD4950) was obtained. Mutational restitution of 14 alpha-demethylation capacity to this derivative resulted in the formation of the 5,6-saturated sterol ergosta-7,22-dien-3 beta-ol as the major product, clearly indicating that 5-desaturase deficiency exists in this demethylation-proficient revertant (KD4952). This implies that its parent, KD4950, which has lost the ability to form the hydroxylated sterol, also is deficient in 5-desaturation. We infer from the results that 5-desaturase is responsible for the formation of the hydroxylated sterol. However, it is unclear whether the hydroxylation represents a genuine step of the normal 5-desaturation reaction.

Congenital glaucoma and Silver-Russell phenotype associated with partial trisomy 7q and monosomy 15q.

We report on a 28-year-old man with trisomy 7q34-qter and monosomy 15q26.3-qter caused by a paternal balanced chromosomal translocation, t(7;15)(q34;q26.3). He had bilateral congenital glaucoma (buphthalmos), as well as typical manifestations of partial trisomy 7q. To our knowledge, this is the second description of a possible relation between congenital glaucoma and 7q trisomy. He also had some Silver-Russell syndrome features, such as short stature of prenatal onset, a characteristic triangular face, clinodactyly of the fifth fingers, and body asymmetry. Fluorescence in situ hybridization analysis on his chromosomes revealed that one copy of the insulin-like growth factor 1 receptor gene (IGF1R) at 15q25-q26 was deleted, suggesting a possible role of IGF1R in the SRS phenotype.

Inactivation of penicillin-induced staphylococcal L-forms by human serum high density lipoprotein.

In penicillin-susceptible bacteria, penicillin causes growth of a small fraction of cells as wall-deficient forms if an appropriate osmoprotection is provided (unstable L-forms). A subfraction of human serum high density lipoprotein (HDL3) was shown to have the ability to inactivate unstable L-forms of Staphylococcus aureus. The active principle was distinguishable from the well-documented trypanosome lytic factor 1 with respect to density, size, and other properties. This L-form cytotoxicity therefore seems to represent a novel antimicrobial entity in human serum.

Rebamipide attenuates nonsteroidal anti-inflammatory drugs (NSAID) induced lipid peroxidation by the manganese superoxide dismutase (MnSOD) overexpression in gastrointestinal epithelial cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) often cause gastrointestinal complications such as gastric ulcers and erosions. Recent studies on the pathogenesis have revealed that NSAIDs induce lipid peroxidation in gastric epithelial cells by generating superoxide anion in mitochondria, independently with cyclooxygenase-inhibition and the subsequent prostaglandin deficiency. Although not clearly elucidated, the impairment of mitochondrial oxidative phosphorylation, or uncoupling, by NSAIDs is associated with the generation of superoxide anion. Physiologically, superoxide is immediately transformed into hydrogen peroxide and diatomic oxygen with manganese superoxide dismutase (MnSOD). Rebamipide is an antiulcer agent that showed protective effects against NSAID-induced lipid peroxidation in gastrointestinal tracts. We hypothesized that rebamipide may attenuate lipid peroxidation by increasing the expression of MnSOD protein in mitochondria and decreasing the leakage of superoxide anion in NSAID-treated gastric and small intestinal epithelial cells. Firstly, to examine rebamipide increases the expression of MnSOD proteins in mitochondria of gastrointestinal epithelial cells, we underwent Western blotting analysis against anti-MnSOD antibody in gastric RGM1 cells and small intestinal IEC6 cells. Secondly, to examine whether the pretreatment of rebamipide decreases NSAID-induced mitochondrial impairment and lipid peroxidation, we treated these cells with NSAIDs with or without rebamipide pretreatment, and examined with specific fluorescent indicators. Finally, to examine whether pretreatment of rebamipide attenuates NSAID-induced superoxide anion leakage from mitochondria, we examined the mitochondria from indomethacin-treated RGM1 cells with electron spin resonance (ESR) spectroscopy using a specific spin-trapping reagent, CYPMPO. Rebamipide increased the expression of MnSOD protein, and attenuated NSAID-induced mitochondrial impairment and lipid peroxidation in RGM1 and IEC6 cells. The pretreatment of rebamipide significantly decreased the signal intensity of superoxide anion from the mitochondria. We conclude that rebamipide attenuates lipid peroxidation by increasing the expression of MnSOD protein and decreasing superoxide anion leakage from mitochondria in both gastric and small intestinal epithelial cells.