NM_000345.3(SNCA):c.157G>A (p.Ala53Thr) AND Parkinson disease 1

Clinical significance:Pathogenic (Last evaluated: Jun 1, 2010)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000015044.25

Allele description [Variation Report for NM_000345.3(SNCA):c.157G>A (p.Ala53Thr)]

NM_000345.3(SNCA):c.157G>A (p.Ala53Thr)

Gene:
SNCA:synuclein alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q22.1
Genomic location:
Preferred name:
NM_000345.3(SNCA):c.157G>A (p.Ala53Thr)
HGVS:
  • NC_000004.12:g.89828149C>T
  • NG_011851.1:g.15148G>A
  • NM_000345.3:c.157G>A
  • NP_000336.1:p.Ala53Thr
  • NC_000004.11:g.90749300C>T
  • P37840:p.Ala53Thr
Protein change:
A53T; ALA53THR
Links:
UniProtKB: P37840#VAR_007454; OMIM: 163890.0001; dbSNP: 104893877
NCBI 1000 Genomes Browser:
rs104893877
Molecular consequence:
  • NM_000345.3:c.157G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Parkinson disease 1 (PARK1)
Synonyms:
Parkinson disease 1, autosomal dominant
Identifiers:
MedGen: C1868595; OMIM: 168601

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000035300OMIMno assertion criteria providedPathogenic
(Jun 1, 2010)
germlineliterature only

PubMed (10)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD).

Vaughan JR, Farrer MJ, Wszolek ZK, Gasser T, Durr A, Agid Y, Bonifati V, DeMichele G, Volpe G, Lincoln S, Breteler M, Meco G, Brice A, Marsden CD, Hardy J, Wood NW.

Hum Mol Genet. 1998 Apr;7(4):751-3.

PubMed [citation]
PMID:
9499430

Low frequency of alpha-synuclein mutations in familial Parkinson's disease.

Farrer M, Wavrant-De Vrieze F, Crook R, Boles L, Perez-Tur J, Hardy J, Johnson WG, Steele J, Maraganore D, Gwinn K, Lynch T.

Ann Neurol. 1998 Mar;43(3):394-7.

PubMed [citation]
PMID:
9506559
See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000035300.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (10)

Description

In affected members of a large Italian family with an early-onset form of autosomal dominant Parkinson disease (PARK1; 168601), and in 3 other unrelated Greek families, Polymeropoulos et al. (1997) demonstrated a heterozygous ala53-to-thr (A53T) mutation in the SNCA gene, resulting from a 209G-A transition. The mutation generates a novel Tsp45I restriction site in the gene.

Vaughan et al. (1998) studied all 7 exons of the SNCA gene in 30 European and American Caucasian kindreds affected with autosomal dominant PD and found no instance of the A53T mutation or any other mutation. In a large screening of patients with PD, Farrer et al. (1998) also found no genetic variation in the SNCA gene. Ho and Kung (1998) failed to find the A53T missense mutation in 118 Chinese sporadic PD patients from Hong Kong or 124 control subjects. They also did not find the mutation in 9 sporadic PD cases from Birmingham, U.K., or 10 control subjects from the same area.

Athanassiadou et al. (1999) studied 19 unrelated families, each of which contained at least 2 first- or second-degree relatives affected with PD. A heterozygous A53T mutation was detected in 10 patients belonging to 7 autosomal dominant families, but was not found in any member of the remaining 12 families. In patients carrying the mutation, the mean age at onset of the disorder was 47 +/- 11 years, which was considered to be early onset. In 1 family, a patient with a much later age at onset of the disease, 76 years, did not carry the A53T mutation.

In the southern Italian kindred originally reported by Polymeropoulos et al. (1997) and the 7 Greek families that carried the A53T mutation, Athanassiadou et al. (1999) studied 10 polymorphic markers. A shared haplotype was considered consistent with a founder chromosome. Clinically, the A53T cases, in addition to early age at onset, showed prominent bradykinesia and muscular rigidity but rarely had tremor. All 7 Greek families with PD studied by Athanassiadou et al. (1999) originated from 3 villages of the northern Peloponnese in Greece; 6 of the families were from 2 villages only 17 km apart. The Italian kindred came from southern Italy, a region geographically and historically linked to Greece.

Spira et al. (2001) reported a family of Greek origin with 5 of 9 sibs affected with PD, 3 of whom were examined in detail and were found to carry the A53T mutation. The 3 sibs presented in their forties with progressive bradykinesia and rigidity, which was initially dopa-responsive, and cognitive decline. Additional features included central hypoventilation, postural hypotension, bladder incontinence, and myoclonus. Neuropathologic examination showed depigmentation of the substantia nigra, severe cell loss and gliosis in the brainstem, and multiple alpha-synuclein-immunopositive Lewy neurites. Cortical neuritic changes associated with tissue vacuolization were present, mostly in the medial temporal regions.

Ki et al. (2007) identified a heterozygous A53T mutation in a Korean man with early-onset PD at age 37 years. A clinically unaffected 45-year-old brother also carried the mutation. The brothers' mother had onset of PD at age 63 years and died at age 67; mutation analysis was not performed. Haplotype analysis showed that this mutation occurred on a different haplotype from that described in Greek and Italian individuals.

Choi et al. (2008) identified the A53T mutation in 1 of 72 unrelated Korean patients with onset of Parkinson disease before age 50. Family history was consistent with autosomal dominant inheritance.

Puschmann et al. (2009) reported 2 affected members of a Swedish family with the A53T mutation. Haplotype analysis indicated a different haplotype than the Greek founder haplotype, suggesting a de novo event in the Swedish family. The proband had insidious onset of decreased range of motion, stiffness, and hypokinesia between ages 39 and 41 years. About 6 months later, she developed word-finding difficulty and monotone speech. The disorder was progressive, and she developed dementia and severe motor disturbances, including myoclonus, by age 47. Her father developed motor signs of the disorder at age 32, with speech difficulties at age 33. At age 38, he was moved to a nursing home, and at 40, he was aphonic with dementia and an inability to walk or feed himself independently. Both patients had normal brain MRI and increased CSF protein levels, SPECT scan of the daughter showed decreased blood flow in the language region. Puschmann et al. (2009) emphasized the early onset, rapid progression, and presence of dementia in this family, and suggested that an underlying cortical encephalopathy contributed to the disease course.

Voutsinas et al. (2010) performed studies on lymphoblastoid cells derived from a female PD patient who was heterozygous for the A53T mutation. RT-PCR showed that the mutant A53T protein was not expressed, and there was only monoallelic expression of the normal SNCA allele. Treatment of her cells with a chromatin modifier resulted in reactivation of the silenced mutant allele, indicating that an epigenetic effect, likely via histone modification, was responsible for the silencing. There was no evidence for changes in methylation. Compared to normal individuals, the patient had an average of a 2-fold increase in total SNCA mRNA. The findings indicated an overall imbalance of allelic expression of the SNCA gene, with the normal allele expressed at a higher level than normal. The report was consistent with the observation that overexpression of the wildtype SNCA gene (see, e.g., 163890.0005) can also cause Parkinson disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 30, 2017