Myotubular myopathy and centronuclear myopathies (CNM) are congenital myopathies characterized by generalized muscle weakness and mislocalization of muscle fiber nuclei. Genetically distinct forms exist, and mutations in BIN1 were recently identified in autosomal recessive cases (ARCNM). Amphiphysins have been implicated in membrane remodeling in brain and skeletal muscle. Our objective was to decipher the pathogenetic mechanisms underlying different forms of CNM, with a focus on ARCNM cases. In this study, we compare the histopathological features from patients with X-linked, autosomal recessive, and dominant forms, respectively, mutated in myotubularin (MTM1), amphiphysin 2 (BIN1), and dynamin 2 (DNM2). We further characterize the ultrastructural defects in ARCNM muscles. We demonstrate that the two BIN1 isoforms expressed in skeletal muscle possess the phosphoinositide-binding domain and are specifically targeted to the triads close to the DHPR-RYR1 complex. Cardiac isoforms do not contain this domain, suggesting that splicing of BIN1 regulates its specific function in skeletal muscle. Immunofluorescence analyses of muscles from patients with BIN1 mutations reveal aberrations of BIN1 localization and triad organization. These defects are also observed in X-linked and autosomal dominant forms of CNM and in Mtm1 knockout mice. In addition to previously reported implications of BIN1 in cancer as a tumor suppressor, these findings sustain an important role for BIN1 skeletal muscle isoforms in membrane remodeling and organization of the excitation-contraction machinery. We propose that aberrant BIN1 localization and defects in triad structure are part of a common pathogenetic mechanism shared between the three forms of centronuclear myopathies.

Recently intronic and exonic mutations in the Tau gene have been found to be associated with familial neurodegenerative syndromes characterized not only by a predominantly frontotemporal dementia but also by the presence of neurological signs consistent with the dysfunction of multiple subcortical neuronal circuitries. Among families, the symptomatology appears to vary in quality and severity in relation to the specific Tau gene mutation and often may include parkinsonism, supranuclear palsies, and/or myoclonus, in addition to dementia. We carried out molecular genetic and neuropathological studies on two patients from a French family presenting, early in their fifth decade, a cognitive impairment and supranuclear palsy followed by an akinetic rigid syndrome and dementia. The proband died severely demented 7 years after the onset of the symptoms; currently, his brother is still alive although his disease is progressing. In both patients, we found a Tau gene mutation in exon 10 at codon 279, resulting in an asparagine to lysine substitution (N279K). Neuropathologically, widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain stem nuclei as well as in the white matter were the hallmark of the disease. These deposits were shown by immunohistochemistry and immunoelectron microscopy, using a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes present in multiple tau regions. In the neocortex, tau-immunopositive glial cells were more numerous than immunopositive neurons; the deeper cortical layers as well as the white matter adjacent to the cortex contained the largest amount of immunolabeled glial cells. In contrast, some brain stem nuclei contained more neurons with tau deposits than immunolabeled glial cells. The correlation of clinical, neuropathological and molecular genetic findings emphasize the phenotypic heterogeneity of diseases caused by Tau gene mutations. Furthermore, to test the effect of the N279K mutation and compare it with the effect of the P301L exon 10 mutation on alternative splicing of Tau exon 10, we used an exon amplification assay. Our results suggest that the N279K mutation affects splicing similar to the intronic mutations, allowing exon 10 to be incorporated more frequently in the Tau transcript.

Polyclonal antibodies exclusively recognizing A beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These demonstrated that FAD-linked presenilins similarly affect both p342 and A beta 42, suggesting that these mutations misroute the beta APP to a compartment where gamma-secretase, but not alpha-secretase, cleavages are modified. Overall, these antibodies should prove useful for fundamental and diagnostic approaches, as suggested by their usefulness for biochemical, cell biological, and immunohistochemical techniques.

Gerstmann-Strä ussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP).

No abstract