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Case Reports
. 2021 Aug:89:63-72.
doi: 10.1016/j.parkreldis.2021.06.023. Epub 2021 Jun 29.

A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

Christina Fevga  1 , Yangshin Park  2 , Ebba Lohmann  3 , Anneke J Kievit  1 , Guido J Breedveld  1 , Federico Ferraro  1 , Leon de Boer  1 , Rick van Minkelen  1 , Hasmet Hanagasi  4 , Agnita Boon  5 , Wei Wang  2 , Gregory A Petsko  6 , Quyen Q Hoang  2 , Murat Emre  4 , Vincenzo Bonifati  7
Affiliations
Case Reports

A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

Christina Fevga et al. Parkinsonism Relat Disord. 2021 Aug.

Abstract

Introduction: Missense variants and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson's Disease (PD).

Methods: Two families of Turkish origins with PD were studied; the SNCA coding region was analyzed by Sanger sequencing, and by whole exome sequencing (WES) in the index patient of the first and the second family, respectively. Co-segregation studies and haplotype analysis across the SNCA locus were carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein.

Results: We identified a novel heterozygous SNCA variant, c.215C > T (p.Thr72Met), segregating with PD in a total of four members in the two families. A shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common ancestor. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. In silico analysis of a tetrameric α-syn structural model revealed that Threonine 72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially destabilize the tetramer.

Conclusion: We present clinical, genetic, and functional data supporting a causative role of the SNCA c.215C > T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the PD-causing SNCA missense variants, and how they lead to neurodegeneration.

Keywords: Late-onset; Parkinsonism; Phenotype; SNCA; Thr72Met; Variant; α-syn.

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Figures

Fig. 1.
Fig. 1.
Pedigrees and segregation analysis. A- and B- Pedigrees of Family 1 (F1) and Family 2 (F2), respectively, harbouring the SNCA c.215C > T (p.Thr72Met) variant. Filled black symbols indicate PD patients, white symbols unaffected members, and green halos around symbols show subjects with polyneuropathy (HMSN2). Arrows indicate the index cases. All the available genotypes for the SNCA c.215C and LRSAM1 c.2005G positions are given for each of the tested family members. AAO: onset age of PD; AAD: age at death; AAE: age at last examination; n. k.: not known; SNCA: SNCA c.215C > T (p.Thr72Met); LRSAM1: LRSAM1 c.2005G > T (p.Glu669*); +/−: heterozygous carrier; −/−: non-carrier. C- Representative electropherogram of one PD case shows the heterozygous SNCA c.215C > T (p.Thr72Met) variant, as compared to reference (wild-type) sequence.
Fig. 2.
Fig. 2.
Haplotype analysis. Genotyping across the SNCA locus reveals a haplotype shared among the tested SNCA carriers, indicated in dark green. Allele counts and frequencies in the 56 Turkish individuals are also shown. Genomic positions are annotated according to the Genome Reference Consortium human genome build 38 (GRCh38). NA: not available; -: absent.
Fig. 3.
Fig. 3.
alpha-Synuclein (α-syn) aggregation assay and in silico structural modelling. A- Thioflavin-T aggregation assay of wild-type α-syn (blue) and α-syn-Thr72Met variant (red). B- and C- Structural models of the α-syn monomer and tetramer, showing the position of the Thr72 residue.
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