Fuchs, J. et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68, 916-922

Department of Psychiatry, Lund University, Lund, Skåne, Sweden
Neurology (Impact Factor: 8.29). 04/2007; 68(12):916-22. DOI: 10.1212/01.wnl.0000254458.17630.c5
Source: PubMed


The "Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjönes in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree.
Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([123]I)-beta-CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records.
The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of <0.9 Mb encompassing alpha-synuclein and multimerin 1 (SNCA-MMRN1), flanked by long interspersed repeat sequences (LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha-synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex.
Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA-MMRN11 multiplication, but whereas SNCA-MMRN1 duplication in the Swedish proband (Branch J) leads to late-onset autonomic dysfunction and parkinsonism, SNCA-MMRN1 triplication in the Swedish American family (Branch I) leads to early-onset Parkinson disease and dementia.

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Available from: Owen A Ross, Jan 17, 2014
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    • "To date, no GWAS or large-scale association studies have been published for MSA. Genomic multiplication of the SNCA locus has been observed to cause parkinsonism, dementia and autonomic dysfunction, characteristic of the MSA phenotype [17]. "
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    • "Interestingly, it is known that a Swedish family with SNCA duplication and a Swedish American family with triplication were descended from a common ancestor [15]. Genetic analysis of this large pedigree indicates a duplication event occurred at first through recombination, and subsequently triplication was generated by unequal crossing-over [15]. This result suggests a possible conversion to triplication could occur in the future generations of duplication families. "
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    • "Whole-locus multiplications seem to lead Abbreviations: AAV, adeno-associated virus; aSyn, alpha-synuclein; ANOVA, analysis of variance; BSA, bovine serum albumin; CBA, chicken β-actin; DA, dopamine; DAergic, dopaminergic; DAPI, 4,6-diamidino-2-phenylindole; DIV, day in vitro; DMEM, Dulbecco's modified Eagle's medium; GAP-43, growth associated protein 43; GDNF, Glial cell line-derived neurotrophic factor; MDN, midbrain dopaminergic neurons; PBS, phosphate-buffered saline; PFA, paraformaldehyde ; PD, Parkinson's disease; ROCK, rho kinase; RT, room temperature; SNpc, Substantia nigra, pars compacta; TH, tyrosine hydroxylase; WT, wildtype. to an earlier and more severe onset of disease depending on the gene copy number (Fuchs et al., 2007). The A53T variant has broadly varying phenotypes and is neuropathologically characterized by DAergic cell loss and a dense burden of aSyn neuritic pathology including axonal spheroids and rare Lewy bodies with fibrillar aSyn-immunoreactive aggregates (Duda et al., 2002). "
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