Previous studies have failed to identify mutations in the Wilson’s disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson’s disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson’s disease phenotype is therefore very low. We report the first cases with Wilson’s disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson’s disease in two consecutive generations. We determined the genetic prevalence of Wilson’s disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson’s disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10^-16 for Class 1 variants or P < 5 × 10^-11 for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson’s disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson’s disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson’s disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.

Here, Tain et al. describe the genetic interaction between 4E-BP, an inhibitor of translation, with Parkinson's disease–associated park and Pink1 in Drosophila, where the manipulation of 4E-BP reduced the pathologic phenotypes, including degeneration of dopaminergic neurons, in park and Pink1 mutant flies. Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.

Objective: The LRRK2^G2019S mutation is the most common identifiable cause for Parkinson disease (PD), but the underlying mechanisms leading to neuronal cell death remain largely unclear. Impaired mitochondrial function and morphology have been described in different in vivo and in vitro model systems of early-onset PD (EOPD) as well as in EOPD patient tissue. The aim of our study was to assess mitochondrial function and morphology in LRRK2^G2019S mutant patient tissue to determine whether impaired mitochondrial function and morphology are shared features in early-onset and late-onset PD. Methods: Skin biopsies were taken from 5 patients with PD with the LRRK2^G2019S mutation. Assessment of mitochondrial membrane potential and intracellular ATP levels as well as substrate-linked mitochondrial ATP production assays were all carried out on 3 independent cell preparations per patient. Results were compared to 5 age-matched controls. Mitochondrial elongation and interconnectivity was assessed using previously published methods. Results: Both mitochondrial membrane potential and total intracellular ATP levels were decreased in the G2019S mutation carriers. Subsequently undertaken mitochondrial ATP production assays suggested that the observed reduction is at least partially due to impaired mitochondrial function. Mitochondrial elongation and interconnectivity were increased in the LRRK2^G2019S patient cohort. Conclusion: Our results provide evidence for impaired mitochondrial function and morphology in LRRK2^G2019S mutant patient tissue. Further studies are required to determine whether the impaired mitochondrial function is due to increased LRRK2 kinase activity or other mechanisms such as LRRK2 haploinsufficiency.