Relative Immunogenicity and Tolerogenicity of Individual Regions or Segments of the MHC

Mixed lymphocyte culture (MIX) reactivity, induction of cytotoxicity in vitro, survival of skin allografts, and induction of neonatal transplantation tolerance were compared in mice of the strain combinations differing in the entire H-2 complex or in individual segments of it. The results showed that antigenic products of the K end of the H-2 complex were more immunogenic and also more resistant to tolerance induction than the products of the D end of H-2. I-region products that elicited transplantation reactions of variable strength, depending on the detection system, were relatively easier to overcome in tolerance induction and could, at least in some combinations, contribute to tolerance induction across the barrier represented by the products of the K region of the H-2 complex.     

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Molecular genetics of familial parkinsonism

Parkinson's disease (PD) is a progressive, neurodegenerative disorder associated with tremor, rigidity, bradykinesia, and postural instability. There exists a familial form of PD that is indistinguishable from the sporadic form. In addition, there exists a class of syndromes classified as parkinsonism-plus syndromes (PPS), in which parkinsonism is an essential but not the only phenotypic characteristic. The etiology of PD remains unclear. Both environmental and genetic factors contribute to the disease pathogenesis. Recent progress in the molecular genetics of parkinsonism has demonstrated that six different chromosomal regions are associated with forms of familial parkinsonism. Mutations in four candidate genes have been identified and include both point mutations and deletions. Both gain-of-function and loss-of-function mutational mechanisms have been implicated. The molecular genetic characterization has led to a new classification of PD and PPS based on the type of genetic defect. Understanding the mechanisms by which these mutations lead to disease should provide further insights into the etiology of parkinsonism.     

Enterostomy in Patients with Primary Neuropathic Amyloidosis

Three patients with primary neuropathic amyloidosis are reported. They were all almost totally disabled by either diarrhea and incontinentia alvi or obstipation. In all three patients enterostomies were tried as a palliative treatment and the results of the operations have been very promising.     

VPS35 and DNAJC13 disease-causing variants in essential tremor

Exome-sequencing analyses have identified vacuolar protein sorting 35 homolog (VPS35) and DnaJ (Hsp40) homolog, subfamily C, member 13 (DNAJC13) harboring disease-causing variants for Parkinson disease (PD). Owing to the suggested clinical, pathological and genetic overlap between PD and essential tremor (ET) we assessed the presence of two VPS35 and DNAJC13 disease-causing variants in ET patients. TaqMan probes were used to genotype VPS35 c.1858G>A (p.(D620N)) (rs188286943) and DNAJC13 c.2564A>G (p.(N855S)) (rs387907571) in 571 ET patients of European descent, and microsatellite markers were used to define the disease haplotype in variant carriers. Genotyping of DNAJC13 identified two ET patients harboring the c.2564A>G (p.(N855S)) variant previously identified in PD patients. Both patients appear to share the disease haplotype previously reported. ET patients with the VPS35 c.1858G>A (p.(D620N)) variants were not observed. Although a genetic link between PD and ET has been suggested, DNAJC13 c.2564A>G (p.(N855S)) represents the first disease-causing variant identified in both, and suggests the regulation of clathrin dynamics and endosomal trafficking in the pathophysiology of a subset of ET patients.