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VPS35-Related Parkinson Disease

Synonym: PARK17

, MD, , PhD, and , MD.

Author Information

Initial Posting: .

Estimated reading time: 21 minutes

Summary

Clinical characteristics.

VPS35-related Parkinson disease (VPS35-PD) is defined as Parkinson disease caused by heterozygous VPS35 pathogenic variants. Currently, the only known VPS35 variant with confirmed pathogenicity is c.1858G>A (p.Asp620Asn). Except for a younger age of onset, VPS35-PD is clinically indistinguishable from Parkinson disease of unknown cause (so-called sporadic Parkinson disease). Variability among 50 individuals reported with molecularly confirmed VPS35-PD includes age of onset (mean: 51.0±8.7 years; range: 34-68 years), Parkinson subtype (tremor, akinetic rigid, mixed), first motor symptom, course of the disease (unilateral onset and slow disease progression are typical; dyskinesia and motor fluctuations may occur), and presence/absence of neuropsychiatric manifestations (including depression, schizophrenia, learning difficulties, mild cognitive impairment, and dementia).

Diagnosis/testing.

The diagnosis of VPS35-PD is established in a proband with at least two cardinal manifestations of Parkinson disease and the heterozygous VPS35 pathogenic variant c.1858G>A (p.Asp620Asn) identified on molecular genetic testing.

Management.

Treatment of manifestations: To date, treatment of VPS35-PD does not differ from that of Parkinson disease in general. Drugs to treat motor manifestations include the precursor of dopamine, levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B), anticholinergics, and amantadine. A good response to levodopa is usually seen. Deep brain stimulation to the subthalamic nucleus is effective in treating motor fluctuations or dyskinesia. Effective treatments for neuropsychiatric and autonomic symptoms, which may be disabling, are limited. Patients benefit from physical, occupational, and speech therapies.

Surveillance: Follow-up clinical neurologic evaluations are recommended every three to 12 months (depending on clinical scenario) to assess tremor, hypokinesia, rigidity, gait, cognition, and neuropsychiatric symptoms as well as treatment effectiveness.

Agents/circumstances to avoid: Drugs that may induce or exacerbate parkinsonism include but are not limited to neuroleptics, antidepressants, calcium channel blockers, valproate, lithium, and amiodarone.

Pregnancy management: No reports have addressed pregnancy management in women with VPS35-PD.

Genetic counseling.

VPS35-PD is inherited in an autosomal dominant manner. About 85% of affected individuals have an affected parent. Although about 15% of affected individuals are simplex cases (i.e., a single occurrence in a family), family data are insufficient to determine if the pathogenic variant is de novo. Each child of an individual with VPS35-PD has a 50% chance of inheriting the VPS35 pathogenic variant. Once the VPS35 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

Diagnostic criteria for Parkinson disease have been published [Berardelli et al 2013, Postuma et al 2015].

Suggestive Findings

VPS35-related Parkinson disease (VPS35-PD) should be considered in individuals with the following clinical and imaging findings (characteristic of all forms of PD) and a family history of PD.

Clinical findings

Cardinal manifestations of Parkinson disease including:

  • Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
  • Hypokinesia (partial or complete loss of muscle movement)
  • Rigidity (increased muscle tone resulting in resistance to passive movement)
  • Disturbance of postural reflexes (which maintain posture during movement)

Additional clinical characteristics:

  • Adult onset
  • Typically unilateral onset
  • Slow disease progression
  • Good response to levodopa therapy

Neuroimaging. Normal cranial MRI

Family history consistent with autosomal dominant inheritance, which can also include simplex cases (i.e., a single occurrence in a family) caused by a de novo pathogenic variant

Establishing the Diagnosis

The diagnosis of VPS35-PD is established in a proband with least two cardinal manifestations of Parkinson disease and the heterozygous VPS35 pathogenic variant c.1858G>A (p.Asp620Asn) identified on molecular genetic testing (see Table 1). Note: To date, this is the only VPS35 variant with confirmed pathogenicity. Other variants have been identified in persons with Parkinson disease but their pathogenicity remains equivocal (see Molecular Genetics).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and genomic testing (comprehensive genome sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of inherited Parkinson disease are largely indistinguishable, most individuals with VPS35-PD are diagnosed by the following recommended testing or testing to be considered.

Recommended Testing

A multigene Parkinson disease panel including VPS35 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Given the rarity of VPS35-related Parkinson disease, some panels for Parkinson disease may not include this gene.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Comprehensive genome sequencing (when clinically available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Single-gene testing (sequence analysis of VPS35) is typically not recommended. Because the phenotype overlaps with that of other inherited forms of Parkinson disease, a multigene panel or exome sequencing are typically used in lieu of single-gene testing.

Table 1.

Molecular Genetic Testing Used in VPS35-Related Parkinson Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
VPS35Sequence analysis 324/24 4, 5
Gene-targeted deletion/duplication analysis 6None reported 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

To date, the pathogenic variant p.Asp620Asn has been found in four simplex cases (i.e., a single occurrence in a family) and 20 probands (index patients) with familial Parkinson disease.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Clinical Characteristics

Clinical Description

To date, 24 probands with molecularly confirmed VPS35-related Parkinson disease (i.e., due to the p.Asp620Asn pathogenic variant) have been reported [Vilariño-Güell et al 2011, Zimprich et al 2011, Ando et al 2012, Kumar et al 2012, Lesage et al 2012, Sharma et al 2012, Sheerin et al 2012]; 20 were familial and four were simplex cases (a single occurrence of VPS35-PD in a family). By testing at-risk relatives in the 20 familial cases, the authors confirmed the diagnosis of VPS35-PD in 26 additional individuals worldwide, bringing to 50 the total of number of individuals with molecularly confirmed VPS35-PD.

Except for a younger age of onset, VPS35-PD is clinically undistinguishable from Parkinson disease of unknown cause. Variability within families with VPS35-PD includes age of onset, first motor symptom, prevailing motor manifestations throughout the course of the disease, and presence/absence of neuropsychiatric manifestations (e.g., depression, dementia).

Age of onset. Mean age at disease onset is 51.0±8.7 years (range: 34-68 years; n=50); 51.2% are female (22/43).

Parkinson subtype. While the tremor-dominant subtype of Parkinson disease (with leg tremor as the initial manifestation) was thought to be common [Wider et al 2008], subsequently reported families had akinetic rigid and mixed subtypes of Parkinson disease, and some individuals never developed tremor [Lesage et al 2012, Sheerin et al 2012].

Course of the disease

  • Asymmetric presentation at disease onset is typical.
  • The disease course is usually slowly progressive.
  • Dyskinesia and motor fluctuations may occur.
    Of note, atypical motor findings, cerebellar signs, or ocular motor signs have not been reported.

Neuropsychiatric manifestations

  • Depression has been reported occasionally; in one family depression was common [Zimprich et al 2011].
  • In one family with VPS35-PD, schizophrenia was reported in two family members with Parkinson disease; however, it was not explicitly stated that the two individuals had been tested for the p.Asp620Asn variant [Wider et al 2008, Vilariño-Güell et al 2011].
  • Learning difficulties, mild cognitive impairment, and dementia have been reported in several affected individuals.

Other findings reported

Functional imaging studies show presynaptic dopaminergic dysfunction, which is apparently indistinguishable from findings in Parkinson disease in general.

Single photon emission computed tomography (SPECT) of cerebral blood flow was normal in one individual [Ando et al 2012].

18F-fluorodopa positron emission tomography (PET) showed asymmetrically reduced striatal 18F-fluorodopa uptake with a posterior predominance [Wider et al 2008].

[123I]-FP-CIT SPECT showed asymmetric tracer uptake [Zimprich et al 2011].

Transcranial sonography. In one individual with Parkinson disease that started with resting tremor on the left side, transcranial sonography performed after a disease course of about 15 years showed normal echogenicity of the left substantia nigra, whereas the bone window was insufficient to allow visualization on the right side [Kumar et al 2012].

Genotype-Phenotype Correlations

No genotype-phenotype correlation is possible as p.Asp620Asn is the only confirmed pathogenic variant to date.

Penetrance

The penetrance of the p.Asp620Asn variant is high and age dependent [Trinh et al 2014, Lill 2016]. Of note, to date data are too limited to allow quantification of penetrance.

Age-dependent penetrance (onset range: 34-68 years) is most likely reflected in the following information on ten unaffected individuals heterozygous for the p.Asp620Asn variant identified in families with VPS35-PD:

The p.Asp620Asn variant is very rare and was not found in:

Nomenclature

VPS35-related Parkinson disease is also referred to as "PARK-VPS35" per the alternative nomenclature system proposed by Marras et al [2012].

Prevalence

To date 24 probands with VPS35-related Parkinson disease have been reported worldwide [Vilariño-Güell et al 2011, Zimprich et al 2011, Ando et al 2012, Kumar et al 2012, Lesage et al 2012, Sharma et al 2012, Sheerin et al 2012]. Twenty were familial and four were simplex cases (a single occurrence of VPS35-PD in a family). By testing relatives at risk in the 20 familial cases, the authors confirmed the diagnosis of VPS35-PD in an additional 26 individuals.

Nine studies with sample sizes greater than 500 patients with PD are available. They comprise a total of 19,294 individuals. In these nine studies, the VPS35 p.Asp620Asn variant was identified in 12 familial index cases and three simplex cases [Vilariño-Güell et al 2011, Zimprich et al 2011, Ando et al 2012, Guo et al 2012, Kumar et al 2012, Sharma et al 2012, Sheerin et al 2012, Zhang et al 2012, Chen et al 2013].

The prevalence of VPS35-PD ranged from 0.0% to 1.5% in the following specific patient populations, which only included persons with familial PD:

In one study (including both familial and simplex cases) heterozygote frequencies were 2:120 in Yemenite Jews and 1:199 in Tunisians [Vilariño-Güell et al 2011].

The p.Asp620Asn variant was not found in 11 studies involving individuals with sporadic and familial Parkinson disease from Europe, the US, South Africa, China (4 studies), and India [Deng et al 2012, Guo et al 2012, Verstraeten et al 2012, Zhang et al 2012, Chen et al 2013, Nuytemans et al 2013, Sudhaman et al 2013, Blanckenberg et al 2014, Kalinderi et al 2015, Bandrés-Ciga et al 2016, Török et al 2016].

The frequency of the VPS35 p.Asp620Asn variant in the general (control) population is very low, and not exactly determined.

Differential Diagnosis

The differential diagnosis of VPS35-related Parkinson disease (VPS35-PD) includes Parkinson disease of unknown cause (sometimes referred to as idiopathic or sporadic Parkinson disease). Apart from a younger age at onset, the phenotype of VPS35-PD (onset at age 50.2±8.9 years) is clinically indistinguishable from sporadic Parkinson disease (average onset at 60 years). Thus, the differential diagnosis of VPS35-PD is the same as it is for PD in general (see Parkinson Disease Overview). In addition, an extensive list of differential diagnosis of familial parkinsonism can be found in the book chapter by Fujioka & Wszolek [2014].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VPS35-related Parkinson disease, the following evaluations are recommended:

  • Perform neurologic examination including assessment of tremor, hypokinesia, rigidity, postural reflexes, gait (propulsion, arm swing, stride length), and autonomic findings (e.g., orthostasis).
  • Assess cognitive function and psychiatric manifestations (e. g., hallucinations, delusions, depression, anxiety, sleep disorders).
  • Evaluate levodopa response.
  • Consider consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

To date, the treatment of individuals with VPS35-PD does not differ from that of Parkinson disease in general. The following is a brief summary of recommended treatment for PD, based on extensive existing guidelines and recommendations for pharmacotherapy of motor and non-motor manifestations of PD as well as neurosurgical interventions for motor findings [Zesiewicz et al 2010, Oertel et al 2011a, Oertel et al 2011b, Seppi et al 2011, Ferreira et al 2013, Odin et al 2015, Trenkwalder et al 2015].

Pharmacotherapy. Drugs to treat motor manifestations include the precursor of dopamine, levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B), anticholinergics, and amantadine. A good levodopa response was seen in nearly all reported individuals with VPS35-PD.

General recommendations for treatment of Parkinson disease of unknown cause include the following:

  • To reduce or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa and dopaminergic medication, doses should not exceed the levels required for a satisfactory clinical response. In younger patients, dopamine agonists should be given a preference.
  • Dyskinesias can be treated with reduction of levodopa doses, use of dopamine receptor agonists, deep-brain stimulation, and continuous application of levodopa or apomorphine.
  • Patients treated with ergot-derived dopamine agonists require periodic echocardiograms. Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are revealed [Antonini & Poewe 2007].

Deep brain stimulation to the subthalamic nucleus was repeatedly reported to be effective in the treatment of disabling motor fluctuations or dyskinesia in persons with VPS35-PD.

Other. Overall, effective treatment for neuropsychiatric and autonomic symptoms (which may be disabling) is limited. Atypical neuroleptic agents such as low-dose clozapine and reduction of dopaminergic therapy can decrease delusions and hallucinations. If depression occurs, it should be treated according to guidelines. Droxidopa may be used to treat orthostasis.

Patients also benefit from physical, occupational, and speech therapy.

Surveillance

For VPS35-PD (as well as in Parkinson disease in general), follow-up clinical neurologic evaluations are recommended every three to 12 months (depending on the clinical scenario and the needs of the individual) to assess tremor, hypokinesia, rigidity, gait, cognition, and neuropsychiatric symptoms as well as treatment effectiveness.

Agents/Circumstances to Avoid

Neuroleptic drugs may increase the severity of parkinsonism in VPS35-PD (as in Parkinson disease in general). In general, atypical neuroleptics are less likely to exacerbate parkinsonism than typical neuroleptics. Other drugs that may induce or exacerbate parkinsonism include but are not limited to antidepressants, calcium channel blockers, valproate, lithium, and amiodarone [Bondon-Guitton et al 2011, Bohlega & Al-Foghom 2013].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Reports addressing pregnancy management in women with VPS35-PD are not available. The effect of PD in general on pregnancy has not been well characterized, since pregnancy is uncommon in women with PD. While most reports indicate that disease manifestations worsen during pregnancy, improvement has also been described (for a review see Robottom et al [2008], Kranick et al [2010]).

No long-term outcome data exist for children born to mothers with Parkinson disease.

  • Levodopa crosses the placenta and some animal models have shown that high doses of levodopa administered during pregnancy may induce skeletal and visceral malformations; however, in more than 30 cases reported in the literature, levodopa treatment during human pregnancy did not result in adverse fetal outcome [Scott & Chowdhury 2005].
  • Amantadine should be avoided during pregnancy, if possible, since adverse pregnancy outcomes have been reported in rats.

Discussion of the risks and benefits of using a given medication during pregnancy should ideally take place prior to conception. See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

VPS35-related Parkinson disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • About 85% of individuals diagnosed with VPS35-PD have an affected parent. Intrafamilial variability is seen in age of disease onset, first motor symptom, prevailing motor manifestations, and presence/absence of neuropsychiatric manifestations (e.g., depression, dementia).
  • About 15% of individuals with VPS35-PD represent simplex cases (i.e., a single occurrence in a family); however, the parents of these individuals have not been evaluated sufficiently to determine if the pathogenic variant occurred de novo in the proband. Therefore, the proportion of VPS35-PD caused by a de novo pathogenic variant is unknown. Of note: Because the p.Asp620Asn variant is known to occur on different haplotypes, it is likely a mutational hot spot.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. No instances of germline mosaicism have been reported, although it is theoretically possible.
  • The family history of some individuals diagnosed with VPS35-PD may appear to be negative because of failure to recognize the disorder in family members, age-related or reduced penetrance of the disease in a heterozygous parent, or early death of the parent before the onset of disease manifestations. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband has the VPS35 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. The risk to sibs who inherit the VPS35 pathogenic variant of developing disease increases with age (see Penetrance).
  • The sibs of a proband with clinically unaffected parents are still at increased risk for VPS35-PD because of the possibility of age-related or reduced penetrance in a parent.
  • If the VPS35 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband

  • Each child of an individual with VPS35-PD has a 50% chance of inheriting the VPS35 pathogenic variant.
  • The probability that an offspring who has inherited a pathogenic variant will become symptomatic increases with age (see Penetrance).

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the VPS35 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic, at-risk individuals)

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Note: It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of VPS35-PD.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the VPS35 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Parkinson Disease Association (APDA)
    135 Parkinson Avenue
    Staten Island NY 10305
    Phone: 800-223-2732 (toll-free); 718-981-8001
    Fax: 718-981-4399
    Email: apda@apdaparkinson.org
  • Fox Trial Finder
  • Michael J. Fox Foundation for Parkinson's Research
    Church Street Station
    PO Box 780
    New York NY 10008-0780
    Phone: 800-708-7644 (toll-free)
    Email: info@michaeljfox.org
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • Parkinson's Foundation
    200 SE 1st Street
    Suite 800
    Miami FL 33131
    Phone: 800-4PD-INFO (473-4636)
    Email: contact@parkinson.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

VPS35-Related Parkinson Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for VPS35-Related Parkinson Disease (View All in OMIM)

601501VPS35 RETROMER COMPLEX COMPONENT; VPS35
614203PARKINSON DISEASE 17; PARK17

Molecular Genetic Pathogenesis

Gene structure. VPS35 consists of approximately 29.6 kb with 17 exons. Reference sequences are listed in Table 2.

Pathogenic variants. The c.1858G>A (p.Asp620Asn) variant in exon 15 is the only variant detected with confirmed evidence of pathogenicity. Because this variant is known to occur on different haplotypes, it is likely a mutational hot spot.

Additional missense variants in VPS35 found in at least one individual with Parkinson disease are listed in Table 2. Because the few missense variants found in multiple individuals with Parkinson disease (p.Gly51Ser, p.Pro316Ser, p.Leu774Met) have also been found in controls, the data are currently insufficient to determine pathogenicity of these variants [Vilariño-Güell et al 2011, Zimprich et al 2011, Sharma et al 2012, Verstraeten et al 2012, Nuytemans et al 2013].

Table 2.

VPS35 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Of uncertain significancec.151G>Ap.Gly51SerNM_018206​.5
NP_060676​.2
c.171G>Ap.Met57Ile
c.723T>Gp.Ile241Met
c.946C>Tp.Pro316Ser
c.1520A>Tp.Tyr507Phe
c.1570C>Tp.Arg524Trp
c.1679T>Cp.Ile560Thr
c.1796A>Gp.His599Arg
c.1819A>Gp.Met607Val
c.2210C>Tp.Ala737Val
c.2320C>Ap.Leu774Met
c.2359G>Ap.Glu787Lys
Pathogenicc.1858G>Ap.Asp620Asn

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. VPS35 encodes a 796-amino-acid protein with a molecular mass of 92 kd termed VPS35. The VPS35 protein is part of the retromer, an evolutionarily conserved complex that associates with the cytosolic face of endosomes. The retromer is involved in the retrograde transport of transmembrane cargo (receptors, including dopamine receptors, transporters, adhesion molecules, and other proteins) from endosomes to the trans-Golgi network and to the plasma membrane; its cargo proteins are either recycled or degraded.

The human retromer comprises two assembling subunits: one consists of a trimeric complex of VPS35, VPS26, and VPS29 proteins and is also termed cargo-selective complex, and the other consists of a sortin nexin dimer (SNX). VPS35 forms a horseshoe-shaped alpha-helical solenoid predicted to contain 33 helices [Lucas et al 2016]. It functions as the central platform for binding to other retromer proteins. VPS35 also mediates the association with the WASH complex, which includes FAM21. FAM21 binds to VPS35 through its extended unstructured "tail" domain, thereby allowing WASH-dependent retromer-mediated sorting of proteins (for a review see Burd & Cullen [2014]).

Abnormal gene product. VPS35 encoding p.Asp620Asn has been shown to fold correctly and to bind VPS29 and VPS26A normally; however, binding to FAM21 of the WASH complex was perturbed, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [Follett et al 2014, McGough et al 2014, Zavodszky et al 2014a, Zavodszky et al 2014b]. Of note, perturbed binding to FAM21 is compatible with a partial loss-of-function variant.

In addition, p.Asp620Asn has been shown to:

  • Redistribute endosomes to a perinuclear localization [Follett et al 2014];
  • Enlarge endosomes [Follett et al 2014];
  • Disrupt the trafficking of cathepsin D, a lysosome protease responsible for degradation of α-synuclein [Follett et al 2014];
  • Lose its ability to interact with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [Wang et al 2016].

VPS35 encoding p.Arg524Trp (which remains to be proven to be pathogenic) resulted in the accumulation of intracellular α-synuclein-positive aggregates, while the retromer showed decreased endosomal association and impaired protein trafficking [Follett et al 2016].

In animal models, p.Asp620Asn results:

  • In mouse: in a reduction of dopamine release in the caudate putamen of homozygous VPS35 p.Asp620Asn knock-in mice [Ishizu et al 2016];
  • In rat: in marked degeneration of substantia nigra dopaminergic neurons, and axonal pathology [Tsika et al 2014];
  • In Drosophila: in poor mobility, shortened life span, and increased sensitivity to rotenone [Wang et al 2014].

VPS35 haploinsufficiency was found to increase Alzheimer disease neuropathology in mice [Wen et al 2011].

References

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Chapter Notes

Acknowledgments

AD is supported by the Max Kade foundation and the gift from Carl Edward Bolch, Jr and Susan Bass Bolch. This work is also supported by NINDS R01 NS078086 (OAR). ZKW is partially supported by the NIH/NINDS P50 NS072187, NIH/NIA (primary) and NIH/NINDS (secondary) 1U01AG045390-01A1, Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C and Sarah K Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch Jr and Susan Bass Bolch, the Sol Goldman Charitable Trust, and Donald G and Jodi P Heeringa.

Revision History

  • 10 August 2017 (bp) Review posted live
  • 15 December 2016 (ad) Original submission
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