Mitochondrial Sequence Variation in African-American Primary Open-Angle Glaucoma Patients

Primary open-angle glaucoma (POAG) is a major cause of blindness and results from irreversible retinal ganglion cell damage and optic nerve degeneration. In the United States, POAG is most prevalent in African-Americans. Mitochondrial genetics and dysfunction have been implicated in POAG, and potentially pathogenic sequence variations, in particular novel transversional base substitutions, are reportedly common in mitochondrial genomes (mtDNA) from POAG patient blood. The purpose of this study was to ascertain the spectrum of sequence variation in mtDNA from African-American POAG patients and determine whether novel nonsynonymous, transversional or other potentially pathogenic sequence variations are observed more commonly in POAG cases than controls. mtDNA from African-American POAG cases (n = 22) and age-matched controls (n = 22) was analyzed by deep sequencing of a single 16,487 base pair PCR amplicon by Ion Torrent, and candidate novel variants were validated by Sanger sequencing. Sequence variants were classified and interpreted using the MITOMAP compendium of polymorphisms. 99.8% of the observed variations had been previously reported. The ratio of novel variants to POAG cases was 7-fold lower than a prior estimate. Novel mtDNA variants were present in 3 of 22 cases, novel nonsynonymous changes in 1 of 22 cases and novel transversions in 0 of 22 cases; these proportions are significantly lower (p<.0005, p<.0004, p<.0001) than estimated previously for POAG, and did not differ significantly from controls. Although it is possible that mitochondrial genetics play a role in African-Americans’ high susceptibility to POAG, it is unlikely that any mitochondrial respiratory dysfunction is due to an abnormally high incidence of novel mutations that can be detected in mtDNA from peripheral blood.     

Differential delay of reinnervating axons alters specificity in the rat serratus anterior muscle

Previous studies have shown remarkable rostrocaudal selectivity by regenerating motoneurons to the rat serratus anterior (SA) muscle after freezing, crushing, or sectioning the long thoracic (LT) nerve. The LT nerve contains motoneurons from both the sixth and seventh cervical spinal nerves (C6 and C7), with C6 motoneurons as the major source of innervation throughout the muscle, and with C7 motoneurons innervating a larger percentage of muscle fibers caudally than rostrally. To determine if synaptic competition can play a role in neuromuscular topography, both the LT nerve and the branch carrying C6 (rostral) motoneurons to the LT nerve were crushed in newborn rats. This approach provides a temporal advantage to regenerating C7 (caudal) motoneurons. After an initial period during which C7 motoneurons reinnervated a larger proportion of muscle fibers than normal in all SA muscle sectors, C6 motoneurons regained their original proportion of rostral muscle fibers. Caudally, however, C7 motoneurons maintained an expanded territory. With this two-site crush method, the number of C6 motoneurons that reinnervate the SA muscle was significantly decreased from normal, whereas the number of C7 motoneurons remained the same. It is concluded that when C7 motoneurons are given a temporal advantage, synaptic specificity can be altered transiently in rostral muscle sectors and permanently in caudal sectors, and this is correlated with a disproportionate loss of C6 motoneurons. Moreover, this may be an important model for studies of synaptic competition, where terminals destined to be eliminated can be identified beforehand. © 1995 John Wiley & Sons, Inc.