caa a22 4500 445364718 CHVBK 20180317142926.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s10048-011-0293-6 doi (NATIONALLICENCE)springer-10.1007/s10048-011-0293-6 Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA -associated Parkinson's disease [Elektronische Daten] [Ziv Gan-Or, Anat Bar-Shira, Tanya Gurevich, Nir Giladi, Avi Orr-Urtreger] 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 (5.1-5.9years younger, p = 0.002-0.01). A significantly higher frequency of early-onset PD (<50years) 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. Springer-Verlag, 2011 Parkinson's disease nationallicence GBA nationallicence Glucocerebrosidase nationallicence MTX1 nationallicence Gan-Or Ziv The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel aut Bar-Shira Anat The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel aut Gurevich Tanya Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel aut Giladi Nir Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel aut Orr-Urtreger Avi The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel aut neurogenetics Springer-Verlag 12/4(2011-11-01), 325-332 1364-6745 12:4<325 2011 12 10048 https://doi.org/10.1007/s10048-011-0293-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10048-011-0293-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gan-Or Ziv The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel aut NATIONALLICENCE 700 1- Bar-Shira Anat The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel aut NATIONALLICENCE 700 1- Gurevich Tanya Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel aut NATIONALLICENCE 700 1- Giladi Nir Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel aut NATIONALLICENCE 700 1- Orr-Urtreger Avi The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel aut NATIONALLICENCE 773 0- neurogenetics Springer-Verlag 12/4(2011-11-01), 325-332 1364-6745 12:4<325 2011 12 10048 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer