Validity and utility of a LRRK2 G2019S mutation test for the diagnosis of Parkinson's disease

The G2019S mutation in the LRRK2 gene, the most common known cause of Parkinson's disease (PD), will soon be widely available as a molecular clinical test for PD. The objective of this study was to assess performance characteristics of G2019S as a clinical test for PD in the setting of typical movement disorder clinics in the United States. Subjects included 1,518 sequentially recruited PD patients from seven movement disorder clinics in the United States, and 1,733 unaffected subjects. All 3,251 subjects were genotyped for the G2019S mutation using a TaqMan assay, and mutations were verified by direct sequencing. Test validity estimates were calculated using standard methods. A total of 20/1518 patients and 1/1733 controls carried the G2019S mutation. Specificity was 99.9% (95% CI, 99.6-100%), sensitivity was 1.3% (0.8-2.1%), and the positive likelihood ratio was 22.8. A positive family history of PD increased the positive likelihood ratio to 82.5. Information on gender, age at disease onset, or age at testing did not improve test performance. The gene test was highly accurate in classifying mutation carriers as PD, but it performed poorly in predicting the phenotype of non-mutation carriers. A G2019S molecular test for PD would be highly specific, technically simple, and inexpensive. Test interpretation is straightforward when used for diagnosis of symptomatic individuals, but is more complex for risk assessment and predictive testing in asymptomatic individuals. Test results can have psychological, social, and economical ramifications; thus, proper counseling is essential.     

Genie differentiation in M. m. domesticus populations from Europe, the Middle East and North Africa: geographic patterns and colonization events

Geographic patterns of genie differentiation were investigated in the commensal house mouse subspecies, M. m. domesticus . The analysis by protein electrophoresis of 40 populations throughout Europe, the Middle East and North Africa indicated that genie differentiation was not highly structured on a macrogeographic scale. Mean genie distances between regions showed, however, that populations fell into three levels of differentiation: a low level in southern Europe within which interregional distances were no larger than intraregional ones, an intermediate level between southern European populations and North European and African ones, and finally, a higher level between all the latter and the Middle Eastern populations.
Gene flow estimates indicated that the homogeneity of southern European populations does not result from present high levels of gene flow, but more likely from a very recent ancestry. These data when argumented with the fossil records of mice from the Mediterranean Basin suggest a two-step colonization process, the most recent of which occurred very rapidly and resulted in the multiple founding of populations in southern Europe. The relationship of M. m. domesticus to other subspecies of mice is discussed in relation to introgression and taxonomy.
Microdifferentiation patterns with low levels of within population substructuring and of gene flow suggest that genie differentiation in the western European house mouse is largely determined by genetic drift and/or founder effects. Although historical factors are determinant in the large scale patterns of genie variation in commensal house mice, dispersal by man no longer seems to be a prominent feature moulding the genetic structure of M. m. domesticus .     

The mechanism of interaction of sweet proteins with the T1R2-T1R3 receptor: evidence from the solution structure of G16A-MNEI

The mechanism by which sweet proteins elicit a response on the T1R2-T1R3 sweet taste receptor is still mostly unknown but has been so far related to the presence of "sweet fingers" on the protein surface able to interact with the same mechanism as that of low molecular mass sweeteners. In the search for the identification of sweet fingers, we have solved the solution structure of G16A MNEI, a structural mutant that shows a reduction of one order of magnitude in sweetness with respect to its parent protein, MNEI, a single-chain monellin. Comparison of the structures of wild-type monellin and its G16A mutant shows that the mutation does not affect the structure of potential glucophores but produces a distortion of the surface owing to the partial relative displacement of elements of secondary structure. These results show conclusively that sweet proteins do not possess a sweet finger and strongly support the hypothesis that the mechanism of interaction of sweet-tasting proteins with the recently identified T1R2-T1R3 GPC receptor is different from that of low molecular mass sweeteners.