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

Abstract

Objective: To study the possible association of founder mutations in the lysosomal storage disorder genes HEXA, SMPD1, and MCOLN1 (causing Tay-Sachs, Niemann-Pick A, and mucolipidosis type IV diseases, respectively) with Parkinson disease (PD).Methods: Two PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that included a total of 938 patients, were studied: a cohort of 654 patients from Tel Aviv, and a replication cohort of 284 patients from New York. Eight AJ founder mutations in the HEXA, SMPD1, and MCOLN1 genes were analyzed. The frequencies of these mutations were compared to AJ control groups that included large published groups undergoing prenatal screening and 282 individuals matched for age and sex.Results: Mutation frequencies were similar in the 2 groups of patients with PD. The SMPD1 p.L302P was strongly associated with a highly increased risk for PD (odds ratio 9.4, 95% confidence interval 3.9-22.8, p , 0.0001), as 9/938 patients with PD were carriers of this mutation compared to only 11/10,709 controls. Conclusions:The SMPD1 p.L302P mutation is a novel risk factor for PD. Although it is rare on a population level, the identification of this mutation as a strong risk factor for PD may further elucidate PD pathogenesis and the role of lysosomal pathways in disease development.

Secretory sphingomyelinase in health and disease

“…Interestingly, there is growing support for a genetic convergence of lysosomal storage disorders and Parkinson's disease (Deng et al, 2014). Mutations such as p.L304P (Gan-Or et al, 2013), which may be limited to Ashkenazi Jews (Wu et al, 2014), or variants in SMPD1, e.g., p.R591C, p.P533L (Foo et al, 2013), have not only been associated with altered ASM activities but also appear to be linked to an up to 9-fold increased risk for Parkinson's disease (Spatola and Wider, 2014). This effect is likely mediated via ceramide because plasma ceramide and monohexosylceramide levels are increased and associated with cognitive impairment in Parkinson's disease patients lacking a risk-conveying glucocerebrosidase mutation (Mielke et al, 2013).…”

LRRK2 deficiency impacts ceramide metabolism in brain

“…Moreover, Cer modulate processes that involve intracellular organelles such as autophagy [9] or mitochondrial-mediated apoptosis [10]. Other lines of evidence link Cer balance to PD pathogenesis: first, mutations in GBA1 and SMPD1, encoding two enzymes that regulate the ceramide salvage pathway, cause inherited forms of lysosomal storage disorders (LSDs) characterized by LB inclusions and neurodegeneration [11,12] and, second, common variants in these genes have been identified as risk factors for PD [13].…”

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

“…The SMPD1 p.L302P is a founder mutation causing Niemann-Pick type A disease among Ashkenazi Jews and a risk factor for PD in this population. 1 In contrast, this specific mutation was never described in the Taiwanese population. Until 2009, no NiemannPick patients with SMPD1 mutations were identified in Taiwan, and then only one patient with compound heterozygous genotype (p.P330R/p.A451D) was described.…”

“…Ruey-Meei Wu, Chin-Hsien Lin, Han-I Lin, Taipei, Taiwan: Gan-Or et al 1 replicated data on a large number of patients with Parkinson disease (PD) in 2 Ashkenazi Jewish cohorts. We would suggest that the authors obtain data from other populations to support the pathogenic role of SMPD1 in the risk of PD.…”