Submission Details

PRKN (also known as Parkin or PARK2) was first reported in relation to autosomal-recessive Parkinson´s disease in 1998 (Kitada et al. 1998, PMID: 9560156). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine-producing neurons in the substantia nigra. Signs and symptoms include tremor, which is most pronounced during rest, muscle rigidity, slowing of voluntary movements (bradykinesia), and a tendency to fall back (postural instability). Many PRKN pathogenic variants in the biallelic state have been reported in >1000 patients by different authors/groups from different ethnicities (Kasten et al. 2018, PMID: 29644727, www.mdsgene.org). The mutational spectrum is broad, often including structural variants (e.g. exon deletions), nonsense, frameshift, splice site, and missense changes. Four multiplex families from three publications are included in this curation, covering patients with biallelic truncating variants. The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence (12 pts.) has been reached. The disease follows a recessive mode of inheritance with almost full, but age-dependent penetrance (Deng et al. 2006, PMID: 16476817; Qin et al. 2014, PMID: 25404955; www.medgene.org). Notably, there is an ongoing debate on the potential role of heterozygous variants as genetic risk factors for Parkinson´s disease (Klein et al. 2007, PMID: 17582365; Zhu et al. 2022, PMID: 35640906). The gene-disease association is also supported by recurrent experimental evidence, including animal models and in-vitro functional assays. The mechanism of pathogenicity appears to be a loss-of-function (LOF) indicated by the many truncating variants and further supported by knock-out fly models (Greene et al., PMID: 12642658). There is a well-defined functional interaction with another autosomal-recessive Parkinson´s disease-linked gene, i.e. PINK1. While PINK1 functions as a sensor for disrupted mitochondria, the PRKN-encoded Parkin protein as an E3-ubiquitin ligase is involved in labeling such mitochondria for degradation (Narendra et al. 2010, PMID: 20126261; Rakovic et al. 2010, PMID: 20508036). It has further repeatedly been shown that several of the PRKN missense variants have impaired ubiquitination properties and impair proper mitophagy (e.g. Sriram et al. 2005, PMID: 16049031; Hampe et al. 2006, PMID: 16714300; Lee et al. 2010; PMID: 20457763; Chaugule et al. 2011, PMID: 21694720; Yi et al. 2019, PMID: 30994895). PRKN overexpression was shown to rescue the phenotype in PINK1 mutant flies (Park et al. 2006, PMID: 16672980). In summary, biallelic, pathogenic variants in PRKN are definitively causing autosomal-recessive Parkinson´s disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.