67 research outputs found
Comparative genetic analysis: the utility of mouse genetic systems for studying human monogenic disease
One of the long-term goals of mutagenesis programs in the mouse has been to generate mutant lines to facilitate the functional study of every mammalian gene. With a combination of complementary genetic approaches and advances in technology, this aim is slowly becoming a reality. One of the most important features of this strategy is the ability to identify and compare a number of mutations in the same gene, an allelic series. With the advent of gene-driven screening of mutant archives, the search for a specific series of interest is now a practical option. This review focuses on the analysis of multiple mutations from chemical mutagenesis projects in a wide variety of genes and the valuable functional information that has been obtained from these studies. Although gene knockouts and transgenics will continue to be an important resource to ascertain gene function, with a significant proportion of human diseases caused by point mutations, identifying an allelic series is becoming an equally efficient route to generating clinically relevant and functionally important mouse models
Biochemical Abnormalities of Muscle Ribosomes During Attacks of Hyperkalemic Periodic Paralysis
Three familial cases (a mother and 2 sons) with hyperkalemic periodic paralysis are presented. Myotonia (orbicularis oculi and hands) was noted all 3 cases. Exposure to cold produced weakness in the 2 older patients. An oral KCl loading test induced paroxysmal weakness in all 3 cases. Ribosomes isolated in 2 cases from biopsied muscle during the induced attacks showed definite increases of protein synthesis in a group of rather heavy muscle polyribosomes. Electron microscopy revealed in both cases scattered small membrane-bound vacuoles, subsarcolemmal aggregates of myotubules, glycogen particles and occasional filamentous bodies
Centronuclear Myopathy: Disease Entity or a Syndrome?. Light- and Electron-Microscopic Study of Two Cases and Review of the Literature
Centronuclear myopathy is a form of hereditary myopathy with onset during gestational life, early infancy or rarely in childhood. Most patients are born as floppy infants. Various skeletal muscles are involved in the disease process. Ptosis, external ophthalmoplegia as well as facial diplegia, and paresis of masticatory, deglutition and speech muscles are common findings. The muscle weakness may rarely show a tendency to improve or to remain stationary, but in most cases, slow and insidious progression occurs. A few cases show no or only minimal handicaps but most of the patients become more or less severely limited in their motor activity. Centronuclear myopathy is characterized by chains of internal nuclei in a high proportion of myofibers. Other histological features vary somewhat from case to case. Centronuclear myopathy is genetically heterogeneous and various patterns of inheritance have been observed. The various genetic types do not differ in their clinical manifestations and anatomical lesions and thus represent true genocopies
The Role of the Gap Junction Protein Connexin32 in the Myelin Sheath
X-linked Charcot-Marie-Tooth disease (CMTX) is caused by mutations in the gap junction gene connexin32 (Cx32). To date, 89 different mutations have been found, including deletions, insertions, missense, and nonsense mutations, and at least two mutations in the non-coding region. Different mutations appear to have different effects on the synthesis and localization of Cx32 protein. Both myelinating Schwann cells and oligodendrocytes express Cx32 mRNA and protein, and the localization of Cx32 protein matches the location of putative gap junctions previously seen by freeze-fracture electron microscopy. In myelinating Schwann cells, Cx32 protein is found in incisures and paranodes. Preliminary data suggest that gap junctions form a radial channel that directly traverses the myelin sheath. It is plausible that mutations in Cx32 disrupt the gap junctions in the myelin sheath, thereby abolishing this radial pathway and leading to peripheral neuropathy
THE RELATIONS BETWEEN OLFACTORY AND VESTIBULAR SENSORY IMPULSES AND TEMPORAL LOBE EPILEPSY
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