title: Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA-associated Parkinson's disease.
abstract: 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.
authors.affiliation: The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Gan-Or
authors.forename: Anat
authors.initials: A
authors.lastname: Bar-Shira
authors.forename: Tanya
authors.initials: T
authors.lastname: Gurevich
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis / Q000379:methods; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: C093550:MTX1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D011506:Proteins; D005962:Glucosylceramidase