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

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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.

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Acknowledgments

This work was supported by Tel Aviv Sourasky Medical Center Grant of Excellence, by the Kahn Foundation, by the Chief Scientist Israel Ministry of Health (grant no. 3–4893), by the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation (grant no.1922/08), and by Michael J Fox and Wolfson Foundations. We thank Dr. Dani Berkovich for his assistance with the DHPLC analysis. This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Ziv Gan-Or, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Declaration

The experiments done in this manuscript comply with the current laws of Israel, in which they were performed. The Institutional and National Supreme Helsinki Committees for Genetic Studies approved the study protocols and the informed consent forms.

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv, 64239, Israel

    Ziv Gan-Or, Anat Bar-Shira & Avi Orr-Urtreger

  2. Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Tanya Gurevich & Nir Giladi

  3. The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Ziv Gan-Or, Tanya Gurevich, Nir Giladi & Avi Orr-Urtreger

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  1. Ziv Gan-Or
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  2. Anat Bar-Shira
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Correspondence to Avi Orr-Urtreger.

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Gan-Or, Z., Bar-Shira, A., Gurevich, T. et al. Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA-associated Parkinson's disease. Neurogenetics 12, 325–332 (2011). https://doi.org/10.1007/s10048-011-0293-6

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