Structural and functional consequences of succinate dehydrogenase subunit B mutations.

Mitochondrial dysfunction, due to mutations of the gene encoding succinate dehydrogenase (SDH), has been implicated in the development of adrenal phaeochromocytomas, sympathetic and parasympathetic paragangliomas, renal cell carcinomas, gastrointestinal stromal tumours and more recently pituitary tumours. Underlying mechanisms behind germline SDH subunit B (SDHB) mutations and their associated risk of disease are not clear. To investigate genotype-phenotype correlation of SDH subunit B (SDHB) variants, a homology model for human SDH was developed from a crystallographic structure. SDHB mutations were mapped, and biochemical effects of these mutations were predicted in silico. Results of structural modelling indicated that many mutations within SDHB are predicted to cause either failure of functional SDHB expression (p.Arg27*, p.Arg90*, c.88delC and c.311delAinsGG), or disruption of the electron path (p.Cys101Tyr, p.Pro197Arg and p.Arg242His). GFP-tagged WT SDHB and mutant SDHB constructs were transfected (HEK293) to determine biological outcomes of these mutants in vitro. According to in silico predictions, specific SDHB mutations resulted in impaired mitochondrial localisation and/or SDH enzymatic activity. These results indicated strong genotype-functional correlation for SDHB variants. This study reveals new insights into the effects of SDHB mutations and the power of structural modelling in predicting biological consequences. We predict that our functional assessment of SDHB mutations will serve to better define specific consequences for SDH activity as well as to provide a much needed assay to distinguish pathogenic mutations from benign variants.

Surgical treatment of maxillary nerve injuries. The infraorbital nerve.

Although inferior alveolar and lingual nerve injuries appear to occur more often, there are undoubtedly cases of ION injury that require evaluation and possible surgical intervention by the oral and maxillofacial surgeon. Patients with ION injuries will require a neurosensory examination for the determination of the level of sensory impairment, or the localization of pain of peripheral origin (centrally mediated pain will not benefit from peripheral nerve surgery). The surgical management of ION injury might be as relatively simple as decompression of the nerve by reduction of a zygomatic complex fracture, or may require extensive mobilization of the nerve and surrounding soft tissue and bone to allow for primary anastomosis or a nerve autograft. In specific instances, improvement in ION sensory function or alleviation of pain within the distribution of the ION can be expected.

Targeted CNS expression of interferon-gamma in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development.

Circumstantial and experimental evidence has implicated the immune cytokine interferon-gamma (IFN-gamma) as a key mediator in the pathological changes that are observed in many demyelinating disorders, including the most common human demyelinating disease, multiple sclerosis. To produce an animal model with which to study the effects of IFN-gamma on the CNS, we have generated transgenic mice in which the expression of IFN-gamma has been placed under the transcriptional control of the myelin basic protein (MBP) gene. Transgenic mice generated with this construct have a shaking/shivering phenotype that is similar to that observed in naturally occurring mouse models of hypomyelination (e.g., shiverer, jimpy, quaking), and these transgenic animals have dramatically less CNS myelin than control animals. Reactive gliosis and increased macrophage/microglial F4/80 immunostaining were also observed. Additionally, major histocompatibility complex (MHC) class I and class II mRNA levels were increased in the CNS of MBP/IFN-gamma transgenic mice, and the increase in MHC class I mRNA expression was detected in both white and gray matter regions. Furthermore, cerebellar granule cell migration was abnormal in these animals. These results strongly support the hypothesis that IFN-gamma is a key effector molecule in immune-mediated demyelinating disorders and indicate that the presence of this cytokine in the CNS may also disrupt the developing nervous system.

Impaired peripheral nerve regeneration in a mutant strain of mice (Enr) with a Schwann cell defect.

Schwann cell-axon interactions in the development, maintenance, and regeneration of the normal peripheral nervous system are complex. A previously described transgene-induced insertional mutation (BPFD#36), now referred to as Enervated (Enr), results in disrupted Schwann cell-axon interactions. In this report, after a crush or transection injury to Enr peripheral nerves, we demonstrate impaired nerve regeneration. There are fewer myelinated fibers per mm2 and thinner myelin sheaths surrounding regenerating axons in the nerves of homozygous mutant mice compared to wild type mice at 28 d after crush injury to the sciatic nerve. Abnormal Schwann cell-axon interactions remain in Enr/Enr animals as evidenced by the relatively frequent ultrastructural finding of unmyelinated large diameter axons in the regenerating nerves. Additionally, nerve graft experiments indicate that the impairment in regeneration is due to a Schwann cell defect. Morphologic and morphometric findings in conjunction with molecular analysis of regenerating nerves suggest that the Enr defect causes a disruption in the ability of "early" Schwann cells to differentiate to a more mature phenotype. In mutant homozygous and wild type nerves at 7 d after crush injury there are similar levels of mRNA for the low-affinity nerve growth factor receptor, but in the mutant homozygous regenerating nerves there is 11-fold less mRNA for glial fibrillary acidic protein, a more mature phenotypic marker of Schwann cells. This Schwann cell differentiation defect likely accounts for both the peripheral neuropathy and impaired nerve regeneration observed in Enr mice.

Perioral somesthetic sensibility: do the skin of the lower face and the midface exhibit comparable sensitivity?

Studies of the perioral somatosensory capacities of neurologically normal adults were reviewed to determine whether sensitivities within the mental and infraorbital nerve distributions are comparable. It was found that tactile detection sensitivity, spatial acuity, and sensitivity to warmth are greater on skin sites located on the midface than on the lower face. In contrast, sensitivity to direction of motion and to differences in surface texture may be greater on skin sites located on the lower face. The literature further suggests that sensitivity within the distribution of each nerve varies appreciably. For example, the vermilion of the lips exhibits considerably greater vibrotactile detection sensitivity, spatial acuity, and sensitivity to direction of motion than does the perioral hairy skin. In addition, spatial acuity is notably greater on midline structures. These findings suggest that knowledge of the patterns of spatial variations in perioral tactile sensibilities can be effectively used during neurosensory examination to select control skin sites for comparison with areas of suspected neurosensory impairment and to distinguish apparent pathological alterations in tactile sensitivity from normal regional differences that characterize the perioral complex.

Maximum voluntary closing forces in the upper and lower lips of humans.

Forces generated by facial muscles during speech production have previously been estimated to involve up to 20% of maximum voluntary closing force. The gross nature of this estimate is due, in part, to the complex relationship between muscle contraction and three-dimensional tissue conformation and to the lack of data concerning maximum force. The objective of the present study was to determine the maximum voluntary closing forces for the upper and lower lips in male and female adults. The results indicate the maximum force capabilities for the lower lip to be approximately three times greater than for the upper lip. Male subjects generated significantly greater lip closing forces than female subjects. The large difference between the upper and lower lips as force plants is discussed in relation to speech function and skilled motor behavior.