NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect.

Mitochondrial respiratory chain complex I consists of 44 different subunits and contains 3 functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and axonal peripheral neuropathy. We performed complex I assembly analysis using primary skin fibroblasts of both patients. Reduced complex I abundance and an accumulation of Q-module subassemblies were present in both patients but more pronounced in the severe clinical phenotype patient. The latter displayed additional accumulation of P-module subassemblies, which was not present in the milder-phenotype patient. Lentiviral complementation of both patient fibroblast cell lines with wild-type NDUFA9 rescued complex I deficiency and the assembly defects. Our report further characterizes the phenotypic spectrum of NDUFA9 deficiency and demonstrates that the severity of the clinical phenotype correlates with the severity of the effects of the different NDUFA9 variants on complex I assembly.

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

PURPOSE: To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder. METHODS: Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing. Transmitochondrial cybrids were obtained by fusion of 143B206 TK(-) rho zero cells with patient-derived enucleated fibroblasts. Immunoblotting techniques were applied to study the complex V assembly. RESULTS: A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones. CONCLUSION: We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

Precession and motional slowing of spin evolution in a high mobility two-dimensional electron gas.

Optical spin-dynamic measurements in a high-mobility n-doped GaAs/AlGaAs quantum well show oscillatory evolution at 1.8 K consistent with a quasi-collision-free D'yakonov-Perel'-Kachorovskii regime. Above 5 K evolution becomes exponential as expected for collision-dominated spin dynamics. Momentum scattering times extracted from Hall mobility and Monte Carlo simulation of spin polarization agree at 1.8 K but diverge at higher temperatures, indicating the importance of electron-electron scattering and an intrinsic upper limit for the spin-relaxation rate.

The results of treatment of carcinoma of the uterine cervix using a linear vaginal source and 4 MV X rays.

Between 1960 and 1976, 1645 women with carcinoma of the uterine cervix were treated in the Radiotherapy Department, Edinburgh. In the earlier years the majority of patients were treated using a partially afterloaded radium line source system, combined with 4 MV external irradiation. The radium was later replaced by caesium which, from 1972, was used in a fully afterloaded line source intracavitary applicator. In recent years a computer program has been used to calculate the dose distribution, resulting in improved pelvic dosimetry and a decline in the frequency and severity of radiation reactions. Actuarial survival rates are reported by stage for a 20-year period. The 5-year survival rate for patients with Stage I disease treated by the Edinburgh method was 74.7% (71.5% for the whole group). For patients with Stage II disease, the rates were 57.1% and 51.3% and for those with Stage III disease, the rates were 40.1% and 28.0%.