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The genetic landscape of Parkinson's disease.
Rev Neurol (Paris). 2018 Nov; 174(9):628-643.RN

Abstract

The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B. Clinical and neuropathological variability among genes is great. LRRK2 mutation carriers present a phenotype similar to those with idiopathic PD whereas, depending on the SNCA mutations, the phenotype ranges from early onset typical PD to dementia with Lewy bodies, including many other atypical forms. DNAJC6 nonsense mutations lead to a very severe phenotype whereas DNAJC6 missense mutations cause a more typical form. PRKN, PINK1 and DJ1 cases present with typical early onset PD with slow progression, whereas other AR genes present severe atypical Parkinsonism. RAB39B is responsible for a typical phenotype in women and a variable phenotype in men. GBA is a major PD risk factor often associated with dementia. A growing number of reported genes described as causal genes (DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, and CHCHD2) are still awaiting replication or indeed have not been replicated, thus raising questions as to their pathogenicity. Phenotypic data collection and next generation sequencing of large numbers of cases and controls are needed to differentiate pathogenic dominant mutations with incomplete penetrance from rare, non-pathogenic variants. Although known genes cause a minority of PD cases, their identification will lead to a better understanding their pathological mechanisms, and may contribute to patient care, genetic counselling, prognosis determination and finding new therapeutic targets.

Authors+Show Affiliations

Inserm U1127, CNRS UMR 7225, UPMC université Paris 06 UMR S1127, Sorbonne université, institut du cerveau et de la moelle épinière, ICM, 75013 Paris, France.Inserm U1127, CNRS UMR 7225, UPMC université Paris 06 UMR S1127, Sorbonne université, institut du cerveau et de la moelle épinière, ICM, 75013 Paris, France.Inserm U1127, CNRS UMR 7225, UPMC université Paris 06 UMR S1127, Sorbonne université, institut du cerveau et de la moelle épinière, ICM, 75013 Paris, France; Département de génétique, hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France. Electronic address: alexis.brice@icm-institute.org.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

30245141

Citation

Lunati, A, et al. "The Genetic Landscape of Parkinson's Disease." Revue Neurologique, vol. 174, no. 9, 2018, pp. 628-643.
Lunati A, Lesage S, Brice A. The genetic landscape of Parkinson's disease. Rev Neurol (Paris). 2018;174(9):628-643.
Lunati, A., Lesage, S., & Brice, A. (2018). The genetic landscape of Parkinson's disease. Revue Neurologique, 174(9), 628-643. https://doi.org/10.1016/j.neurol.2018.08.004
Lunati A, Lesage S, Brice A. The Genetic Landscape of Parkinson's Disease. Rev Neurol (Paris). 2018;174(9):628-643. PubMed PMID: 30245141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The genetic landscape of Parkinson's disease. AU - Lunati,A, AU - Lesage,S, AU - Brice,A, Y1 - 2018/09/21/ PY - 2018/08/27/received PY - 2018/08/28/accepted PY - 2018/9/25/pubmed PY - 2019/1/23/medline PY - 2018/9/25/entrez KW - Genetic counselling KW - Genetic risk KW - Genetics KW - Genotype-phenotype correlation KW - Mendelian transmission KW - Parkinson's disease SP - 628 EP - 643 JF - Revue neurologique JO - Rev Neurol (Paris) VL - 174 IS - 9 N2 - The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B. Clinical and neuropathological variability among genes is great. LRRK2 mutation carriers present a phenotype similar to those with idiopathic PD whereas, depending on the SNCA mutations, the phenotype ranges from early onset typical PD to dementia with Lewy bodies, including many other atypical forms. DNAJC6 nonsense mutations lead to a very severe phenotype whereas DNAJC6 missense mutations cause a more typical form. PRKN, PINK1 and DJ1 cases present with typical early onset PD with slow progression, whereas other AR genes present severe atypical Parkinsonism. RAB39B is responsible for a typical phenotype in women and a variable phenotype in men. GBA is a major PD risk factor often associated with dementia. A growing number of reported genes described as causal genes (DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, and CHCHD2) are still awaiting replication or indeed have not been replicated, thus raising questions as to their pathogenicity. Phenotypic data collection and next generation sequencing of large numbers of cases and controls are needed to differentiate pathogenic dominant mutations with incomplete penetrance from rare, non-pathogenic variants. Although known genes cause a minority of PD cases, their identification will lead to a better understanding their pathological mechanisms, and may contribute to patient care, genetic counselling, prognosis determination and finding new therapeutic targets. SN - 0035-3787 UR - https://www.unboundmedicine.com/medline/citation/30245141/The_genetic_landscape_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0035-3787(18)30806-3 DB - PRIME DP - Unbound Medicine ER -
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