Parkinson Disease and Complex Parkinsonism

Gene: HTRA2

One variant, p.G399S initially found using a candidate gene approach in 4 sporadic PD patients; the polymorphism A141S was found at higher frequencies in patients with PD (15961413). In a large case control screen neither of the variants were found to be associated with PD, and they were present in neurologically normal controls (18364387). 18401856 screened 66 Belgian PD patients and 273 control individuals and found one novel mutation in one PD (p.Arg404Trp) and six variants at the 5 and 3 regions in PD. PMID: 18790661 sequenced HTRA2 in 95 probands with apparent autosomal dominant inheritance of Parkinson's disease did not identify any pathogenic mutations. PMID 20036034 performed a large genetic association study (6378 cases and 8880 controls) to evaluate the contribution of Omi/HtrA2 to Parkinson's disease and failed to identify an association of Omi/HtrA2 variants with PD. 21701785 screened a cohort of sporadic PD patients in the taiwanse population and found a missense variant, Pro143Ala was absent in total 850 control subjects. Functional studies suggested a mitochondrial dysfunction in cells carrying the variant. 24337630 screened a cohort of PD (Taiwanese) and found a novel heterozygous mutation, R36W, in one early-onset and two late-onset PD patients, which was absent in 606 normal controls. Functional studies suggested a mitochondrial dysfunction in cells carrying the variant. The p.G399S (mono and bi-allelic) was lately found in a large Turkish family with essential tremor, with some affected developing also parkinsonism (PMID: 25422467), the p.G399S was then genotyped in 204 Parkinson disease, 103 essential tremor patients and in cervical dystonia patients and in controls from Norway and it was not found to be associated with PD or tremor, and it was present in neurologically normal controls. (PMID: 25825781). Overall, these results do not support a major role of HTRA2 in PD.

Created: 14 Dec 2016, 5:27 p.m.

In PMID:15961413, 4 of 518 patients with Parkinson's disease were found a 1195G-A transition (G399S) in exon 7 of the HTRA2 gene. However PMID 18364387 found a similar frequency of the G399S allele among 644 patients and 828 controls. Similarly, PMID:18401856 cast doubts on the pathogenicitiy of the A141S variant identified by PMID:15961413 because of a similar frequencey amongst controls and patients.

Review PMID:23462481 suggests that HTRA2 is a gene with mutations originally thought to cause Parkinson's, but since unconfirmed.

Created: 10 Nov 2016, 4:41 p.m.

Comment on list classification: Discussed with Arianna. Some controversy around this gene, and mixed reports. Should remain red.

Created: 8 Dec 2016, 3:50 p.m.

Comment on list classification: Discussed with Arianna. Some controversy around this gene, and mixed reports. Should remain red.

Created: 8 Dec 2016, 3:50 p.m.

Comment on list classification: Due to uncertainty regarding the pathogenicity of variants within this gene to cause Parkinson's disease, I have demoted this from amber to red.

Created: 15 Nov 2016, 9:54 a.m.

This gene is not mentioned in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual.

Created: 10 Jun 2016, 12:18 p.m.