Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Poornima Jayadev Menon^{1

2

3}, Sara Sambin^{4

5}, Baptiste Criniere-Boizet⁴, Thomas Courtin^{4

6}, Christelle Tesson⁴, Fanny Casse⁴, Melanie Ferrien⁴, Louise-Laure Mariani^{4

5}, Stephanie Carvalho⁴, Francois-Xavier Lejeune⁴, Sana Rebbah⁴, Gaspard Martet⁴, Marion Houot^{4

5

7

8}, Aymeric Lanore^{4

5}, Graziella Mangone^{4

5

9}, Emmanuel Roze^{4

5}, Marie Vidailhet^{4

5}, Jan Aasly¹⁰, Ziv Gan Or^{11

12

13}, Eric Yu^{11

12

13}, Yves Dauvilliers¹⁴, Alexander Zimprich¹⁵, Volker Tomantschger¹⁶, Walter Pirker¹⁷, Ignacio Álvarez¹⁸, Pau Pastor¹⁹, Alessio Di Fonzo²⁰, Kailash P Bhatia²¹, Francesca Magrinelli²¹, Henry Houlden²², Raquel Real^{21

23

24}, Andrea Quattrone^{21

25}, Patricia Limousin²¹, Prasad Korlipara²¹, Thomas Foltynie²¹, Donald Grosset²⁶, Nigel Williams²⁷, Derek Narendra²⁸, Hsin-Pin Lin²⁸, Carna Jovanovic²⁹, Marina Svetel²⁹, Timothy Lynch³⁰, Amy Gallagher³⁰, Wim Vandenberghe³¹, Thomas Gasser^{32

33}, Kathrin Brockmann^{32

33}, Huw R Morris²¹, Max Borsche³⁴, Christine Klein³⁴, Olga Corti⁴, Alexis Brice^{4

6}, Suzanne Lesage⁴, Jean Christophe Corvol^{4

5}; French Parkinson disease Genetics Study Group (PDG)

Affiliations

¹ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France. poornimajmenon@gmail.com.
² Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France. poornimajmenon@gmail.com.
³ School of Postgraduate Studies, Royal College of Surgeons in Ireland, Dublin, Ireland. poornimajmenon@gmail.com.
⁴ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
⁵ Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.
⁶ Assistance Publique Hôpitaux de Paris, Department of Genetics, Hôpital Pitié-Salpêtrière, Paris, France.
⁷ Centre of Excellence of Neurodegenerative Disease (CoEN), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
⁸ Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
⁹ Department of Neurology, Movement Disorder Division, Rush University Medical Center, 1725 W. Harrison Street, Chicago, IL, USA.
¹⁰ Department of Neurology, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
¹² Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
¹³ Department of Human Genetics, McGill University, Montreal, QC, Canada.
¹⁴ Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Institute for Neurosciences of Montpellier (INM), INSERM, Montpellier, France.
¹⁵ Department of Neurology, University Hospital Vienna, Vienna, Austria.
¹⁶ Gailtal-Klinik Hermagor, Hermagor, Austria.
¹⁷ Department of Neurology, Ottakring Clinic, Vienna, Austria.
¹⁸ Department of Neurology, Hospital Universitari Mutua de Terrassa, and Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Barcelona, Spain.
¹⁹ Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
²⁰ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
²² Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
²³ UCL Movement Disorders Centre, University College London, London, UK.
²⁴ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
²⁵ Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
²⁶ Institute of Neurological Sciences, University of Glasgow, Glasgow, UK.
²⁷ Department of Psychological Medicine and Neurology, Cardiff University, Cardiff, UK.
²⁸ Inherited Disorders Unit, Neurogenetics Branch, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
²⁹ University Clinical Center of Serbia, Neurology Clinic, Belgrade, Serbia.
³⁰ The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin Ireland and University College Dublin, Dublin, Ireland.
³¹ Department of Neurology, University Hospitals Leuven; Department of Neurosciences, KU Leuven; Leuven Brain Institute, Leuven, Belgium.
³² Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
³³ DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
³⁴ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

PMID: 38553467
PMCID: PMC10980707
DOI: 10.1038/s41531-024-00677-3

Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Poornima Jayadev Menon et al. NPJ Parkinsons Dis. 2024.

. 2024 Mar 29;10(1):72.

doi: 10.1038/s41531-024-00677-3.

Authors

Affiliations

¹ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France. poornimajmenon@gmail.com.
² Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France. poornimajmenon@gmail.com.
³ School of Postgraduate Studies, Royal College of Surgeons in Ireland, Dublin, Ireland. poornimajmenon@gmail.com.
⁴ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
⁵ Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.
⁶ Assistance Publique Hôpitaux de Paris, Department of Genetics, Hôpital Pitié-Salpêtrière, Paris, France.
⁷ Centre of Excellence of Neurodegenerative Disease (CoEN), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
⁸ Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
⁹ Department of Neurology, Movement Disorder Division, Rush University Medical Center, 1725 W. Harrison Street, Chicago, IL, USA.
¹⁰ Department of Neurology, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
¹² Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
¹³ Department of Human Genetics, McGill University, Montreal, QC, Canada.
¹⁴ Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Institute for Neurosciences of Montpellier (INM), INSERM, Montpellier, France.
¹⁵ Department of Neurology, University Hospital Vienna, Vienna, Austria.
¹⁶ Gailtal-Klinik Hermagor, Hermagor, Austria.
¹⁷ Department of Neurology, Ottakring Clinic, Vienna, Austria.
¹⁸ Department of Neurology, Hospital Universitari Mutua de Terrassa, and Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Barcelona, Spain.
¹⁹ Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
²⁰ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
²² Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
²³ UCL Movement Disorders Centre, University College London, London, UK.
²⁴ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
²⁵ Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
²⁶ Institute of Neurological Sciences, University of Glasgow, Glasgow, UK.
²⁷ Department of Psychological Medicine and Neurology, Cardiff University, Cardiff, UK.
²⁸ Inherited Disorders Unit, Neurogenetics Branch, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
²⁹ University Clinical Center of Serbia, Neurology Clinic, Belgrade, Serbia.
³⁰ The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin Ireland and University College Dublin, Dublin, Ireland.
³¹ Department of Neurology, University Hospitals Leuven; Department of Neurosciences, KU Leuven; Leuven Brain Institute, Leuven, Belgium.
³² Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
³³ DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
³⁴ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

PMID: 38553467
PMCID: PMC10980707
DOI: 10.1038/s41531-024-00677-3

Abstract

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

PubMed Disclaimer

Conflict of interest statement

A.D.F. received honoraria for participating as scientifica board member to advisory board from Sanofi, Bial, Zambon. H.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia and Amylyx; lecture fees/honoraria—BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. H.W.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). Z.G. Or received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Inceptions Sciences (now Ventus), Ono Therapeutics, Bial Biotech, Bial, Handl Therapeutics, UCB, Capsida, Denali Lighthouse, Guidepoint and Deerfield. E.R. was supported by Société Française de Médecine esthétique and Enjoysharing for his work on Parkinson disease. Jean-Christophe Corvol has served in advisory boards for Alzprotect, Bayer, Biogen, Denali, Ferrer, Idorsia, Prevail Therapeutic, Servier, Theranexus, UCB; and received grants from Sanofi. Kailash P. Bhatia has received grant support from Wellcome/MRC, NIHR, Parkinson’s UK and EU Horizon 2020. He receives royalties from the publication of the Oxford Specialist Handbook Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008), of Marsden’s Book of Movement Disorders (Oxford University Press, 2012), and of Case Studies in Movement Disorders—Common and uncommon presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson’s Disease and Movement Disorders Society. H.H. is grateful for the essential support from patients and families and for grateful funding from The Wellcome Trust, The MRC, The MSA Trust, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, The Michael J Fox Foundation (MJFF), BBSRC, The Fidelity Trust, Rosetrees Trust, Ataxia UK, Brain Research UK, Sparks GOSH Charity, Alzheimer’s Research UK (ARUK) and CureDRPLA. D.N. has a research collaboration with Spark Therapeutics for which he receives research funding support. M.B. received honoraria from Ipsen Pharma. L.-L.M. has received research support grants from INSERM, JNLF, The L’Oreal Foundation, the French Parkinson Association, Fondation of France, Paris Brain Institute BBT and Neurocatalyst calls; speech honoraria from CSL, Sanofi-Genzyme, Lundbeck, Teva; consultant for Accure therapeutics, Sanofi and received travel funding from the Movement Disorders Society, ANAINF, Merck, Merz, Medtronic, Teva and AbbVie, outside the submitted work. All other authors declare no financial or non-financial competing interest.

Figures

**Fig. 1. Exonic locations of structural variants identified in the cohort.**
A The exonic locations of deletions identified in the cohort. B The exonic locations of duplications identified in the cohort. N refers to the number of times these variants were identified in the cohort, with the homozygous presence of these variants being counted as N = 2.

**Fig. 2. Lollipop plot demonstrating the Parkin protein domain location of single nucleotide variants identified in the cohort.**
(The size of the lollipop corresponds to the frequency at which variants were identified at these loci).

**Fig. 3. Boxplot demonstrating the average age at onset of *PRKN-*PD based on the type of variant.**
(f/f = frameshift/frameshift, f/m = frameshift/ missense, f/s = frameshift/ structural, m/m = missense/missense, m/s = missense/structural, s/s = structural/structural).

**Fig. 4. Boxplot demonstrating the average age at onset of *PRKN-PD* based on the Parkin protein terminus location of variants.**
(C-terminus = exon 7–12, Middle = exon 3–6, N-terminus = exon 1–2).

**Fig. 5. Linear regression models of motor progression.**
a UPDRS part III (OFF) scores at a given disease duration and (b) LEDD at a given disease duration.

**Fig. 6. Kaplan-Meir survival curves comparing the time in years from first symptom to development of motor complications in *PRKN*-PD and early-onset PD.**
Time to develop (A) motor fluctuations, (B) dyskinesia and (C) freezing in *PRKN*-PD compared to early-onset PD. D Kaplan-Meir survival curve demonstrating the time in years from first symptom to development of postural instability in *PRKN*-PD. (The dashed lines delineate the time by which half of the patients had developed the complication).

See this image and copyright information in PMC

References

1. Polymeropoulos MH, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–2047. doi: 10.1126/science.276.5321.2045. - DOI - PubMed
1. Aasly JO. Long-term outcomes of genetic Parkinson’s disease. J. Mov. Disord. 2020;13:81–96. doi: 10.14802/jmd.19080. - DOI - PMC - PubMed
1. Vollstedt EJ, Kasten M, Klein C. Using global team science to identify genetic Parkinson’s disease worldwide. Ann. Neurol. 2019;86:153–157. doi: 10.1002/ana.25514. - DOI - PMC - PubMed
1. Taghavi S, et al. A clinical and molecular genetic study of 50 families with autosomal recessive Parkinsonism revealed known and novel gene mutations. Mol. Neurobiol. 2018;55:3477–3489. doi: 10.1007/s12035-017-0535-1. - DOI - PMC - PubMed
1. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2012;2:a008888. doi: 10.1101/cshperspect.a008888. - DOI - PMC - PubMed

Grants and funding

ZIA NS003169/ImNIH/Intramural NIH HHS/United States

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Affiliations

Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources