Impaired growth hormone-releasing hormone neurons ultrastructure and peptide accumulation in the arcuate nucleus of mosaic mice with altered copper metabolism.

A progressive decrease in body weight and retarded linear growth observed in mosaic male mice with the mutation linked to X-chromosome (Atp7a(mo-ms)) raised the question whether hypophysiotropic growth axis activity may be affected in these animals. A pathologically developed median eminence ultrastructure with very low somatostatin accumulation as well as an intensive phagocytosis of growth hormone cells observed in the anterior pituitary gland raised the question whether hypothalamic growth hormone-releasing hormone (GHRH) neuronal network is also affected in mosaic mice. In this study an arcuate nucleus GHRH neurons ultrastructure as well as GHRH peptide accumulation in normal and mutant mice were compared. An electron microscopic immunocytochemical method with colloidal-gold labeling was applied to compare the ultrastructural morphology of GHRH neuron and intracellular GHRH peptide distribution. Mosaic mice exhibited a pathologically developed ultrastructure of arcuate nucleus GHRH neurons, defective intracellular peptide localization as well as reduced peptide storage. Obtained results support the crucial role of unaltered copper metabolism in physiological development of hypophysiotropic growth axis activity. Consequently, a pathologically developed GHRH hypothalamic network may impact progressive decrease in body weight and retarded length growth observed in mosaic male mice.

Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography.

Barth syndrome (BTHS) is a mitochondrial disorder that is caused by mutations in the tafazzin gene, which affects phospholipid composition. To determine whether this defect leads to alterations in the internal three-dimensional organization of mitochondrial membranes, we applied electron microscopic tomography to lymphoblast mitochondria from BTHS patients and controls. Tomograms were formed from 50 and 150 nm sections of chemically fixed lymphoblasts and the data were used to manually segment volumes of relevant structural details. Normal lymphoblast mitochondria contained well-aligned, lamellar cristae with slot-like junctions to the inner boundary membrane. In BTHS, mitochondrial size was more variable and the total mitochondrial volume per cell increased mainly due to clusters of fragmented mitochondria inside nuclear invaginations. However, mitochondria showed reduced cristae density, less cristae alignment, and inhomogeneous cristae distribution. Three-dimensional reconstruction of BTHS mitochondria revealed zones of adhesion of the opposing inner membranes, causing obliteration of the intracrista space. We found small isolated patches of adhesion as well as extended adhesion zones, resulting in sheets of collapsed cristae packaged in multiple concentric layers. We also found large tubular structures (diameter 30-150 nm) that appeared to be derivatives of the adhesion zones. The data suggest that mitochondrial abnormalities of BTHS involve adhesions of inner mitochondrial membranes with subsequent collapse of the intracristae space.

X-linked myotubular myopathy with probable germline mosaicism.

X-linked myotubular myopathy is a disorder characterized by severe neonatal hypotonia and respiratory insufficiency. The mutation of MTMI gene results in a defective production of myotubularin, which is responsible for the maturational arrest of muscle development. An identical mutation in the carrier mother and the diseased child establishes the inheritance. We report the disease in a neonate with a mutation on exon 6 of the MTMI gene. Surprisingly, the mother was healthy and did not carry this mutation, she is likely to have germline mosaicism.