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The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease

Ziv Gan-Or1, Laurie J Ozelius, Anat Bar-Shira

  • 1Genetic Institute and Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.

Neurology
|March 29, 2013
PubMed
Abstract

Insights

A specific mutation in the SMPD1 gene (p.L302P) significantly increases the risk of developing Parkinson disease (PD). This finding highlights the role of lysosomal pathways in PD pathogenesis.

Area of Science:

  • Genetics
  • Neuroscience
  • Lysosomal Storage Disorders

Background:

  • Lysosomal storage disorders (LSDs) like Tay-Sachs, Niemann-Pick A, and mucolipidosis type IV are caused by mutations in genes such as HEXA, SMPD1, and MCOLN1.
  • Investigating founder mutations in these LSD genes may reveal novel associations with neurodegenerative diseases.
  • Parkinson disease (PD) pathogenesis is complex and may involve genetic factors beyond those traditionally studied.

Purpose of the Study:

  • To investigate the potential association between founder mutations in HEXA, SMPD1, and MCOLN1 genes and the risk of developing Parkinson disease (PD).
  • To determine if specific mutations common in the Ashkenazi Jewish (AJ) population contribute to PD susceptibility.

Main Methods:

  • Analysis of eight AJ founder mutations in HEXA, SMPD1, and MCOLN1 genes within two PD patient cohorts (total 938 patients) of AJ ancestry.
  • Comparison of mutation frequencies in PD patients with large AJ control groups, including those from prenatal screening and age/sex-matched individuals.

Main Results:

  • The SMPD1 p.L302P mutation showed a strong association with an increased risk of PD (OR 9.4, P < 0.0001).
  • Nine out of 938 PD patients carried the SMPD1 p.L302P mutation, compared to 11 out of 10,709 controls.
  • Mutation frequencies were consistent across the two studied PD patient cohorts.

Conclusions:

  • The SMPD1 p.L302P mutation is identified as a novel risk factor for Parkinson disease.
  • This discovery may offer new insights into PD pathogenesis and the involvement of lysosomal pathways in neurodegeneration.
  • While rare, this mutation's strong association underscores the importance of exploring lysosomal function in PD development.

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