Point Mutations in the α-Synuclein Gene

Abstract

Idiopathic Parkinson’s disease (PD) is an age-dependent, neurodegenerative disorder and is predominantly sporadic. Only 20–30% of patients have a positive family history for PD with a complex mode of inheritance. In a few extended families, the disease is inherited as an autosomal dominant trait. Linkage to chromosome 4 was reported in a large Italian kindred multiply affected by an early-onset form of PD (1). However, this finding was not replicated in a sample of 94 Caucasian families by Scott et al. (2), or in 13 multigenerational families by Gasser et al. (3). It has recently been demonstrated that a mutation within the a-synuclein gene on chromosome 4 segregates with disease in the Italian family (4). It was further demonstrated that the same missense mutation was also present in three Greek families with early onset PD. Sequence analysis of exon 4 of the gene revealed a single base pair change at position 209 from G to A (G209A). This mutation results in an Ala to Thr substitution at position 53 of the protein (Ala53Thr) and creates a Tsp45I restriction site (4). This is the first report of a mutation causing clinically and pathologically defined idiopathic PD associated with the critical pathologic finding, the intraneuronal inclusions called Lewy bodies in brainstem nuclei including the substantia nigra. However, KrÜger et al. (5) reported a G→C transversion at position 88 of the coding sequence in two sibs and the deceased mother in a German family. It was concluded that this mutation is the cause of PD in this family.