Genetics of Parkinson disease and essential tremor

Abstract

Purpose of review Elucidating the genetic background of Parkinson disease and essential tremor is crucial to understand the pathogenesis and improve diagnostic and therapeutic strategies. Recent findings A number of approaches have been applied including familial and association studies, and studies of gene expression profiles to identify genes involved in susceptibility to Parkinson disease. These studies have nominated a number of candidate Parkinson disease genes and novel loci including Omi/HtrA2, GIGYF2, FGF20, PDXK, EIF4G1 and PARK16. A recent notable finding has been the confirmation for the role of heterozygous mutations in glucocerebrosidase (GBA) as risk factors for Parkinson disease. Finally, association studies have nominated genetic variation in the leucine-rich repeat and Ig containing 1 gene (LINGO1) as a risk for both Parkinson disease and essential tremor, providing the first genetic evidence of a link between the two conditions. Summary Although undoubtedly genes remain to be identified, considerable progress has been achieved in the understanding of the genetic basis of Parkinson disease. This same effort is now required for essential tremor. The use of next-generation high-throughput sequencing and genotyping technologies will help pave the way for future insight leading to advances in diagnosis, prevention and cure.

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

“…All patients had all cardinal signs of Parkinson’s disease and all but one had tremor. Psychosis, hallucination and disorientation was noted in patients and first-degree relatives and might partly be explained by medication side effects; none of the patients had any obvious cognitive decline at the time of inclusion (Aasly et al , 2010; Wider et al , 2010). …”

“…Additional mutations in genes for Parkinson’s disease are shown in square brackets. Besides carrying PINK1 p.G411S, both Ukrainian patients were compound heterozygous for PARK2 p.Q34RfsX5/p.R275W mutations that are considered pathogenic, Patient SWE-2 carried a PARK2 p.D394N substitution, for which there is no evidence for an association with Parkinson’s disease, and Patient NOR-13 carried a LRRK2 p.M1646T substitution, which has been shown to increase Parkinson’s disease risk (Wider et al , 2010; Ross et al , 2011). Affected relatives of Patient NOR-13 had an LRRK2 p.N1437H mutation but these individuals did not carry PINK1 p.G411S (Aasly et al , 2010).…”

Interactogeneous: Disease Gene Prioritization Using Heterogeneous Networks and Full Topology Scores

“…Interestingly, the fibroblast growth factor 20 gene ( FGF20 , 12 entries) possessing broad mitogenic and cell survival activities, ranked in the top 10. Variation in FGF20 has been linked to risk for PD, not confirmed by later studies [49]. Among the top 10 were also found ubiquitin C ( UBC , 67 entries) and glutathione S-transferase omega 1 and 2 ( GSTO1 and GSTO2 , 7 entries each), hinted to influence age at onset in PD [55], followed by the heat shock 70 kDa protein 4 ( HSPA4 , 74 entries).…”

Key Issues in Essential Tremor Genetics Research: Where Are We Now and How Can We Move Forward?

“…Another alternate explanation of ET inheritance remains within genetics: ET may be a complex trait, with work to date identifying only a limited amount of the heritable component of ET 15, 22, 36, 45, 116, 121, 145. Uncovering “missing heritability” in ET may require researchers to pursue rare rather than common causal genetics variants, and/or many genetic risk factors 15, 121, 140.…”

“…Uncovering “missing heritability” in ET may require researchers to pursue rare rather than common causal genetics variants, and/or many genetic risk factors 15, 121, 140. As in epigenetics, progress in genetics is often made through advancing technologies.…”