We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

No abstract

No abstract

The degree of pigment dispersal in the xanthophores and melanophores of Gillichthys mirabilis matched the animal to its background. Hypophysectomy did not affect the melanophores, which appear to be under nervous control, but did cause concentration of the pigment in the xanthophores so that the fish could no longer adapt to a yellow background. Acetyl choline had no effect on the pigment cells but epinephrine concentrated the pigment in the melanophores. Prolactin and high doses of ACTH dispersed the pigment in the xanthophores; the main effect of ACTH was indirect and probably due to stimulation of the interrenal tissue. Cortisol dispersed pigment in the xanthophores and concentrated it in the melanophores. 8-MSH also had a n indirect effect in dispersing pigment in the xanthophores. Metyrapone reduced the indirect effect of P-MSH and ACTH but had no effect on the yellowing of fish to match a yellow background. Thus prolactin, rather than the other hormones, appears to be involved in the normal response to a yellow background. The subcutaneous implantation of a single pituitary provided sufficient hormone to affect the overlying xanthophores. Reserpine resulted in pigment dispersal in the xanthophores of intact Gillichthys but had no effect in hypophysectomized fish. This suggests that the release of prolactin is normally controlled by an inhibitory factor from the brain,