ClinVar Genomic variation as it relates to human health

To investigate further the role of alpha-synuclein in familial Parkinson disease (PARK1; 168601), Kruger et al. (1998) undertook mutation analysis of all 5 translated SNCA exons in 192 sporadic cases and in 7 unrelated patients with a family history for Parkinson disease. None of the patients was found to carry the A53T mutation (163890.0001). One patient was found to carry a heterozygous 88G-C transversion in exon 3, resulting in an ala30-to-pro (A30P) substitution. The index patient developed signs of progressive parkinsonism at 52 years of age. His mother presented with symptoms at age 56 and died from the disease at age 60. A younger sib, aged 55, reported impaired motor function in the right arm and neurologic findings of Parkinson disease. The 33-year-old child of the index patient and a 50-year-old sib were carriers of the mutation. Both exhibited subtle neurologic disturbances. The A30P substitution was not found in 1,140 control chromosomes. Kruger et al. (1998) concluded that mutations in the SNCA gene participate in the pathogenesis of some rare cases of Parkinson disease. Kruger et al. (2001) characterized the disease phenotype caused by the A30P mutation and found that it is similar to that of typical PD, including cardinal features of PD and positive and sustained response to L-DOPA therapy. Two affected members of 1 family showed striatal dopaminergic abnormalities on PET scan similar to those in sporadic PD. Cognitive impairment was noted as an early and frequent finding. Seidel et al. (2010) reported neuropathologic findings of a patient with PD due to the A30P mutation. He had onset at age 54 years, had L-DOPA-related complications, and died in a mute, bedridden state at age 69. Postmortem examination showed depigmentation and neuronal loss in the substantia nigra and neuronal loss in the locus ceruleus and dorsal motor vagal nucleus. There were widespread SNCA-positive Lewy bodies, Lewy neurites, and glial aggregates in the cerebral cortex and many other regions of the brain, including the hippocampus, hypothalamus, brainstem, and cerebellum. Biochemical analysis showed a significant load of insoluble SNCA. Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring the A53T alpha-synuclein mutation. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen (Tardiff et al., 2013), and NEDD4 (602278), the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons. (less)