Scientists have pinpointed many gene variants that heighten a person’s risk for Parkinson's, but rarely have they happened upon deletions of whole chromosome fragments. Now, researchers led by Anne Bassett, Centre for Addiction and Mental Health, Toronto, Canada, report that loss of a snippet from chromosome 22 increases the risk of early onset Parkinson's disease (PD). They found a cluster of autopsy-confirmed PD in a cohort of people with a 22q11.2 deletion syndrome, suggesting there might be genes in that region of the chromosome that protect against PD. The results appeared in the September 9 JAMA Neurology online.

"If confirmed, this would be among the first discoveries that genomic microdeletions can contribute to PD susceptibility," wrote Joshua Shulman, Baylor College of Medicine, Houston, Texas, in an accompanying editorial. Some studies have implicated rare microdeletions encompassing the Parkin or tyrosine hydroxylase genes as possible susceptibility factors, Shulman pointed out (see Pankratz et al., 2009 and Bademci et al., 2010). Because current technologies tend to overlook deletions, the role of this chromosomal defect may be underestimated, Shulman added. Microdeletions usually crop one or more entire genes and can be more devastating than point mutations.

Deletions around chromosome 22q11.2 occur spontaneously in at least one in 4,000 people. Sometimes called velocardiofacial or DiGeorge syndrome, 22q11.2 deletion causes congenital and adult-onset disorders such as schizophrenia. Four people with the syndrome were previously diagnosed with PD (see Booij et al. 2010, and Booij et al. 2010), making researchers wonder if the two were linked.

To test this, first author Nancy Butcher and colleagues sorted through medical records of the relatively large and well-characterized 22q11.2 deletion cohort at the Centre for Addiction and Mental Health. Of the 159 people known to this center, four, ranging in age from 44 to 55, had been diagnosed with PD. They began showing motor symptoms between the ages of 39 and 48. Neither the sole 22q11.2 patient over 65, or patients younger than 34, showed any PD-like symptoms. Though the number of patients is small, Bassett estimated that people with the 22q11.2 deletion may have at least a 20-fold greater risk of PD than the general population. More accurate data could come from larger cohorts of 22q11.2 deletion patients, she said.

Brain tissue from the autopsies of three of the four patients with PD confirmed the diagnosis. Dopamine-producing cells of the substantia nigra and striatum had degenerated in all three. However, immunohistochemistry revealed classical Parkinson pathology in only two of them, including cortical and sub-cortical Lewy bodies—aggregates of misfolded protein made up principally of α-synuclein. Autopsy tissue from three PD-free 22q11.2 deletion patients showed no evidence of synuclein pathology or loss of dopamine neurons.

These results have implications both for patients with 22q11.2 deletions and those with PD, Bassett told Alzforum. Clinicians should look carefully for PD symptoms as people with a 22q11.2 deletion age. Complicating matters, PD symptoms can resemble side effects of the antipsychotic medications used to treat schizophrenia, which affects one in four people with 22q11.2 deletions. People with early onset PD should be checked for signs of 22q11.2 deletions, some of which can be managed, said Bassett.

The findings may also point to mechanisms underlying PD pathology, wrote the authors. As in patients with mutations in Parkin and LRRK2, Lewy bodies can be absent in PD linked to 22q11.2 deletion syndrome (for a review, see Poulopoulos et al., 2012). Determining what causes dopaminergic degeneration in the 22q11.2 patients might shed light on neurodegeneration in pathologically similar forms of familial PD, suggested the authors. While the genes for parkin and LRRK2 are on chromosomes 6 and 12, respectively, there are about 50 genes around chromosome 22q11.2 that might alter risk for PD. Candidates include catechol-O-methyltransferase, which is important for breaking down dopamine, DGCR8, which helps process microRNAs in the brain, and microRNA-185, which is predicted to target LRRK2 mRNA. "With the availability of various 22q11-related mouse models generated for previous schizophrenia studies, it would be interesting to interrogate these mice to identify the critical genes involved in the PD-related phenotypes," wrote Huaibin Cai, National Institute on Aging, Bethesda, Maryland, to Alzforum in an email (see full comment below).—Gwyneth Dickey Zakaib


  1. The authors provide convincing evidence that links chromosome 22q11 deletions to PD. Although patients with 22q11 and LRRK2 mutations share many neuropathological abnormalities, it remains to be determined whether they follow similar pathogenic pathways. For example, disease onset is much earlier in the 22q11 cases, and the clinical syndrome is perhaps more severe, too.

    One interesting aspect of 22q11 deletion is the potential impairment of microRNA processing mediated by DGCR8. LRRK2 is shown to regulate microRNA function, too (Gehrke et al., 2010). But we don't know whether DGCR8 and LRRK2 affect a similar subset of microRNAs critical for the function and survival of dopaminergic neurons.

    Based on the algorithm we used, LRRK2 is not a good target for miR-185; however, that needs to be tested experimentally. If miR-185 indeed controls the expression of LRRK2 protein, the alteration of LRRK2 expression may contribute to the pathogenesis of 22q11 deletion. But LRRK2, at best, is just one of the downstream targets for miR-185 or DGCR8. The 22q11 mutation is going to be helpful in understanding the pathogenic mechanism of PD more broadly.

    With the availability of various 22q11-related mouse models generated for the previous schizophrenia studies, it would be interesting to interrogate these mice to identify the critical genes involved in the PD-related phenotypes.


    . Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature. 2010 Jul 29;466(7306):637-41. PubMed.

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Paper Citations

  1. . A rare novel deletion of the tyrosine hydroxylase gene in Parkinson disease. Hum Mutat. 2010 Oct;31(10):E1767-71. PubMed.
  2. . Co-occurrence of early-onset Parkinson disease and 22q11.2 deletion syndrome: Potential role for dopamine transporter imaging. Am J Med Genet A. 2010 Nov;152A(11):2937-8. PubMed.
  3. . The neuropathology of genetic Parkinson's disease. Mov Disord. 2012 Jun;27(7):831-42. PubMed.

External Citations

  1. Pankratz et al., 2009
  2. Booij et al. 2010

Further Reading


  1. . Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4447-52. PubMed.
  2. . Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 Jun;40(6):751-60. PubMed.
  3. . Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A. 2005 Nov 1;138(4):307-13. PubMed.
  4. . Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9. PubMed.
  5. . Familial Parkinson disease mutations influence α-synuclein assembly. Neurobiol Dis. 2011 Sep;43(3):715-24. PubMed.

Primary Papers

  1. . Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome: Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications. JAMA Neurol. 2013 Nov 1;70(11):1359-66. PubMed.
  2. . Structural Variation and the Expanding Genomic Architecture of Parkinson Disease. JAMA Neurol. 2013 Sep 9; PubMed.