Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approachReport as inadecuate

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Human Genetics

, Volume 136, Issue 1, pp 13–37

First Online: 28 November 2016Received: 22 July 2016Accepted: 16 November 2016


Parkinson’s disease PD, the second most common progressive neurodegenerative disorder of aging, was long believed to be a non-genetic sporadic origin syndrome. The proof that several genetic loci are responsible for rare Mendelian forms has represented a revolutionary breakthrough, enabling to reveal molecular mechanisms underlying this debilitating still incurable condition. While single nucleotide polymorphisms SNPs and small indels constitute the most commonly investigated DNA variations accounting for only a limited number of PD cases, larger genomic molecular rearrangements have emerged as significant PD-causing mutations, including submicroscopic Copy Number Variations CNVs. CNVs constitute a prevalent source of genomic variations and substantially participate in each individual’s genomic makeup and phenotypic outcome. However, the majority of genetic studies have focused their attention on single candidate-gene mutations or on common variants reaching a significant statistical level of acceptance. This gene-centric approach is insufficient to uncover the genetic background of polygenic multifactorial disorders like PD, and potentially masks rare individual CNVs that all together might contribute to disease development or progression. In this review, we will discuss literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will analyze the most frequent copy number changes in familiar PD genes and provide a -systems biology- overview of rare individual rearrangements that could functionally act on commonly deregulated molecular pathways. Assessing the global genome-wide burden of CNVs in PD patients may reveal new disease-related molecular mechanisms, and open the window to a new possible genetic scenario in the unsolved PD puzzle.

AbbreviationsABL1ABL proto-oncogene 1, non-receptor tyrosine kinase

ADCYAP1Adenylate cyclase-activating polypeptide 1

ATP13A2ATPase 13A2

ATXN3Ataxin 3


BCL2Apoptosis regulator

CHCHD3Coiled-coil-helix-coiled-coil-helix domain containing 3

CNTNAP2Contactin-associated protein-like 2

CNVsCopy number variations


CUL5Cullin 5

D1RDopamine receptor D1

DACH1Dachshund family transcription factor 1

DDOSTDolichyl-diphosphooligosaccharide–protein glycosyltransferase non-catalytic subunit

DGCR8DGCR8 microprocessor complex subunit

DLC1DLC1 Rho GTPase-activating protein

DLG1Discs large MAGUK scaffold protein 1

DOCK5Dedicator of cytokinesis 5

FBXO7F-box protein 7

FBXW7F-box and WD repeat domain containing 7

FISHFluorescent in situ hybridization

FoSTeSFork stalling and template switching

FPR3Formyl peptide receptor 3

FTLDU-17Ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17

GAK-DGKQCyclin G-associated kinase-diacylglycerol kinase theta

GBAGlucosylceramidase beta

GBAP1Glucosylceramidase beta pseudogene 1

GNB1LG protein subunit beta 1 like

GRID1Glutamate ionotropic receptor delta type subunit 1

GRIP1Glutamate receptor interacting protein 1


HNF1BHNF1 homeobox B

HSF1Heat-shock transcription factor 1

HTRA2HtrA serine peptidase 2

IGF1Insulin growth factor 1

IGF1RInsulin-like growth factor 1 receptor

KCNJ12Potassium voltage-gated channel subfamily J member 12

KLC1Kinesin light chain 1

LHX1LIM homeobox 1

LRRK2Leucine-rich repeat kinase 2

MAPTMicrotubule-associated protein tau

MBD3Methyl–CpG binding domain protein 3

NAHRNon-allelic homologous recombination

NAT8LN-Acetyltransferase 8 like

NHEJNon-homologous end joining

NRSN1Neurensin 1

NRXN1Neurexin 1

NSFN-Ethylmaleimide-sensitive factor, vesicle fusing ATPase

OVOS2Ovostatin 2

PACAPPituitary adenylate cyclase-activating polypeptide

PARK10Parkinson disease 10

PARK12Parkinson disease 12

PARK16Parkinson disease 16

PARK2Parkin RBR E3 ubiquitin protein ligase

PARK3Parkinson disease 3 autosomal dominant, Lewy body

PARK7Parkinsonism-associated deglycase

PCLOPiccolo presynaptic cytomatrix protein

PINK1PTEN-induced putative kinase 1

PLA2G6Phospholipase A2 group VI

PPP1R8Protein phosphatase 1 regulatory subunit 8

PPYR1Neuropeptide Y receptor Y4

PSMG1Proteasome assembly chaperone 1

RTN4RReticulon 4 receptor

RYR2Ryanodine receptor 2

SEPT5Septin 5

SLC5A7Solute carrier family 5 member 7

SNAP29Synaptosome-associated protein 29


SYNJ1Synaptojanin 1

SYT15Synaptotagmin 15

TBX1T-box 1

TCF3Transcription factor 3

THTyrosine hydroxylase

UCHL1Ubiquitin C-terminal hydrolase L1

UPSUbiquitin proteasome system

USP32Ubiquitin-specific peptidase 32

VPS35VPS35 retromer complex component

WNT3Wnt family member 3

5-HT2ARSerotonin 2A receptor

Electronic supplementary materialThe online version of this article doi:10.1007-s00439-016-1749-4 contains supplementary material, which is available to authorized users.

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Author: Valentina La Cognata - Giovanna Morello - Velia D’Agata - Sebastiano Cavallaro


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