Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson's disease

Saini, Prabhjyot; Rudakou, Uladzislau; Yu, Eric; Ruskey, Jennifer A.; Asayesh, Farnaz; Laurent, Sandra B.; Spiegelman, Dan; Fahn, Stanley; Waters, Cheryl; Monchi, Oury; Dauvilliers, Yves; Dupré, Nicolas; Greenbaum, Lior; Hassin‐Baer, Sharon; Espay, Alberto J.; Rouleau, Guy A.; Alcalay, Roy N.; Fon, Edward A.; Postuma, Ronald B.; Gan‐Or, Ziv

doi:10.1016/j.neurobiolaging.2020.10.019

Cited by 22 publications

(16 citation statements)

References 77 publications

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“…Some genes have only been reported in single pedigrees plus isolated cases (e.g., TMEM230 variants [ 75 , 76 ]) or have conflicting presence in healthy controls (e.g., UHCL1 , HTRA2 [ 77 ]). These could represent variants with reduced penetrance or simply erroneous associations with disease.…”

Section: Monogenic Parkinson’s Diseasementioning

confidence: 99%

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Day

Mullin

2021

Genes

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The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.

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Section: Monogenic Parkinson’s Diseasementioning

confidence: 99%

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Day

Mullin

2021

Genes

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“…GIGYF2 (GRB10-interacting GYF protein 2, MIM * 612003; PARK11, MIM#607688), HTRA2 (HTRA serine peptidase 2, MIM * 610297; PARK13, MIM#606441), UCHL1 (ubiquitin carboxyl-terminal esterase L1, MIM * 191342; PARK15, MIM#613643), and EIF4G1 (eukaryotic translation initiation factor 4-G, MIM * 614251; PARK18, MIM#614251) variants were detected in families with late-onset Parkinsonism resembling iPD and segregating with autosomal dominant fashion. However, many studies denied their pathogenic role in PD and none of them is still considered as a PD gene ( 90 , 91 ). With the advent of NGS and the increasing availability of whole exome/genome sequencing (WES/WGS) many genes such as DNAJC13, CHCHD2, TMEM230, LRP10 , and RIC3 have been identified in AD PD families.…”

Section: Introductionmentioning

confidence: 99%

“…Brain pathology of three mutation carriers showed LB with cell loss in Meynert nucleus and SN, as well as tau pathology. However, no other PD cases with pathogenic variants in DNAJC13 have been detected to date and its role in PD etiology has been recently reconsidered ( 91 ). An independent study in the same Mennonite kindred identified the c.422G>T variant in TMEM230 (Transmembrane protein 230, MIM * 617019) as the cause of the Parkinsonism segregating in that family.…”

Section: Introductionmentioning

confidence: 99%

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

et al. 2021

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Parkinson disease (PD) is a complex neurodegenerative disorder, usually with multifactorial etiology. It is characterized by prominent movement disorders and non-motor symptoms. Movement disorders commonly include bradykinesia, rigidity, and resting tremor. Non-motor symptoms can include behavior disorders, sleep disturbances, hyposmia, cognitive impairment, and depression. A fraction of PD cases instead is due to Parkinsonian conditions with Mendelian inheritance. The study of the genetic causes of these phenotypes has shed light onto common pathogenetic mechanisms underlying Parkinsonian conditions. Monogenic Parkinsonisms can present autosomal dominant, autosomal recessive, or even X-linked inheritance patterns. Clinical presentations vary from forms indistinguishable from idiopathic PD to severe childhood-onset conditions with other neurological signs. We provided a comprehensive description of each condition, discussing current knowledge on genotype-phenotype correlations. Despite the broad clinical spectrum and the many genes involved, the phenotype appears to be related to the disrupted cell function and inheritance pattern, and several assumptions about genotype-phenotype correlations can be made. The interest in these assumptions is not merely speculative, in the light of novel promising targeted therapies currently under development.

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“…In contrast to the ATP13A2 p.Ile946Phe variant we identified, predicted to be tolerated and previously described also in a healthy control (35), the novel EIF4G1 p.Ala13Pro variant in the father was predicted to be deleterious by in silico analyses. Although variants in EIF4G1 gene were initially identified in familial and sporadic PD (37,38), their association to PD is now disputed (39). Therefore we can only speculate that the presence the two rare variants in ATP13A2 and EIF4G1 genes may confer a higher risk to the father to develop PD.…”

Section: Discussionmentioning

confidence: 90%

Genetic and epigenetic disease modifiers in an Italian C9orf72 family expressing ALS, FTD or PD clinical phenotypes

Peverelli

D'Adda

Colombrita

et al. 2021

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Objective: The presence of the hexanucleotide repeat expansion (HRE) in C9orf72 gene is associated to the ALS/FTD spectrum, but also to parkinsonisms. We here describe an Italian family with the father diagnosed with Parkinson disease (PD) at the age of 67 and the two daughters developing FTD and ALS at 45 years of age. We searched for C9orf72 HRE with possible genetic and epigenetic modifiers to account for the intrafamilial phenotypic variability. Methods: C9orf72 mutational analysis was performed by fragment length analysis, Repeat-primed PCR and Southern blot. Targeted next generation sequencing was used to analyze 48 genes associated to neurodegenerative diseases. Promoter methylation was analyzed by bisulfite sequencing. Results: Genetic analysis identified C9orf72 HRE in all the affected members with a similar repeat expansion size. Both the father and the FTD daughter also carried the heterozygous p.Ile946Phe variant in ATP13A2 gene, associated to PD. In addition, the father also showed a heterozygous EIF4G1 variant (p.Ala13Pro), that might increase his susceptibility to develop PD. The DNA methylation analysis showed that all the 26 CpG sites within C9orf72 promoter were unmethylated in all family members. Conclusions: Neither C9orf72 HRE size nor promoter methylation act as disease modifiers within this family, at least in blood, not excluding HRE mosaicism and a different methylation pattern in the brain. However, the presence of rare genetic variants in PD genes suggests that they may influence the clinical manifestation in the father. Other genetic and/or epigenetic modifiers must be responsible for disease variability in this C9orf72 family case.

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Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson's disease

Cited by 22 publications

References 77 publications

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

Genetic and epigenetic disease modifiers in an Italian C9orf72 family expressing ALS, FTD or PD clinical phenotypes

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