Our finding suggests that haploinsufficiency of TH
could increase PD risk. Several lines of evidence support this hypothesis. 1) A carrier parent of a child with DRD, with a TH
heterozygous missense mutation (296delT), was noted to have stress induced stiffness (Furukawa et al., 2001
). 2) A heterozygous missense mutation (A6T) in TH
was reported in an early-onset PD patient (age-at-onset of 36). The patient also has a heterozygous duplication of exon 11 in the parkin gene. An additive effect of the two mutations may account for developing PD at an early age-at-onset in this patient (Hertz et al., 2006
). 3) Animal studies have shown that TH
enzyme activity decreases by age. This age-associated change could introduce stress to dopaminergic cells and contribute to the risk of PD posed by aging (De La Cruz et al., 1996
). It is intuitive to propose that haploinsufficiency of the TH
gene leads to a lower level of TH
activity and thus increases PD risk. However, accurate measurement of TH
activity in the brain requires cerebral spinal fluid analysis (Zafeiriou et al., 2009
) and this could not be pursued in this patient.
Our study is an example of how a rare genetic variant could contribute to PD risk. The TH
deletion appears to be very rare: one case with TH
deletion was found after screening 635 PD cases in our study. Liu et al. has screened TH
gene for CNV using Multiplex Ligation-dependent Probe Amplification assays in 16 DRD patients. No deletion was reported, which might be due to the small sample size (Liu et al., 2010
). This highlights the difficulty in studying rare variants: it often requires screening large number of samples.
It has been suggested that a large portion of the genetic contribution to complex diseases, like PD, may be due to rare variants (Bodmer and Bonilla., 2008
). Each rare variant is expected to be found in a small number of individuals. To definitively demonstrate the association between rare variants and a disease can be difficult, often requiring clustering of multiple rare variants in one gene (Bodmer and Bonilla., 2008
), or by conducting a functional study on the rare variant and the gene. In this case, the implication of TH
in PD is well acknowledged. Due to the limited resolution of the current methods for CNV study, it is possible that smaller deletions in TH
exist in PD patients but were not identified in our study. Recent leaps in sequencing technology should help answer this question, and catalogue other rare variants in PD.