Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA-associated Parkinson's disease

Neurogenetics. 2011 Nov;12(4):325-32. doi: 10.1007/s10048-011-0293-6. Epub 2011 Aug 12.


A strong association was established between the GBA gene and Parkinson's disease (PD) worldwide. The most frequent GBA mutation among the Ashkenazi population (p.N370S) was previously associated with the c.1051T>C (p.F351L) alteration in the closely located MTX1 gene. We further studied the association between these two genes and its possible effect on PD. The entire coding region and exon-intron boundaries of MTX1 were analyzed in 81 PD patient carriers of GBA mutations, 15 healthy controls that carry GBA mutations, and in 25 non-carrier patients. Among them, the MTX1 c.184T>A (p.S63T) variation was detected in 93% of GBA mutation carriers (both patients and healthy controls) and in 64% of non-carrier patients (p = 0.0008). This alteration was analyzed in 600 consecutively recruited Ashkenazi PD patients and in 353 controls, all genotyped for the LRRK2 p.G2019S and GBA founder mutations. A significantly higher frequency of the MTX1 c.184A allele was found in carriers of GBA mutations compared to non-carriers (0.67 and 0.45, respectively, p < 0.0001). The homozygous MTX1 c.184A/A genotype was associated with a significantly earlier age of motor symptoms onset in patients with GBA mutations compared to other groups of patients tested (5.1-5.9 years younger, p = 0.002-0.01). A significantly higher frequency of early-onset PD (<50 years) was detected among patients carrying both GBA mutation and the homozygous MTX1 c.184A/A genotype (35.9%, compared to 13.6-17.5%, p = 0.028). Our results raise the possibility that alteration on the opposite allele, which is in trans to the GBA mutant allele, may affect the clinical course of GBA-associated PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset*
  • Aged
  • Alleles
  • Amino Acid Sequence
  • Animals
  • DNA Mutational Analysis / methods
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genotype
  • Glucosylceramidase / genetics*
  • Humans
  • Jews / genetics
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Parkinson Disease / genetics*
  • Proteins / genetics*
  • Sequence Alignment


  • MTX1 protein, human
  • Proteins
  • Glucosylceramidase