PLoS One. 2015 Aug 14;10(8):e0135950. doi: 10.1371/journal.pone.0135950. eCollection 2015.

Parkinson’s Disease in Saudi Patients: A Genetic Study.

Al-Mubarak BR1, Bohlega SA2, Alkhairallah TS2, Magrashi AI1, AlTurki MI1, Khalil DS1, AlAbdulaziz BS1, Abou Al-Shaar H1, Mustafa AE1, Alyemni EA1,Alsaffar BA3, Tahir AI1, Al Tassan NA1.

1Behavioral Genetics unit, Department of Genetics, King Faisal Specialist Hospital and Research Center. P.O Box 3354, Riyadh 11211, Saudi Arabia.

2Department of  Neurosciences, King Faisal Specialist Hospital and Research Center. P.O Box 3354, Riyadh 11211, Saudi Arabia.

3King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia P.O Box 6086, Riyadh 11442,  Saudi Arabia.

*Corresponding author, email: BAl-Mubarak@kfshrc.edu.sa

 

Abstract

Parkinson’s disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.

PMID:26274610 [PubMed – indexed for MEDLINE] PMCID:PMC4537238   Free PMC Article

 

Supplement  

Background 

Parkinson’s disease (PD) is a movement disorder, clinically characterized by the presence of bradykinesia (slowness of movement) and at least one of the other three cardinal motor symptoms (tremor, postural instability or stiffness). The movement dysfunction is due to progressive loss of dopamine releasing neurons in a specific brain region known as the midbrain. The disabilities associated with PD significantly impair the quality of life representing a major socioeconomic burden especially in aging populations [1-3]. Although, available therapies are successful in relieving symptoms, they are ineffective in stopping or even slowing down the disease progression. Therefore, intense effort is being aimed at understanding the mechanisms of this disease and much of it is gained through the study of the monogenic forms.

 

Objective

The main objective of our study is to investigate the genetic causes of PD in Saudi patients with either the familial or sporadic form.

 

Study design

  1. Recruiting PD patients with familial and sporadic forms of the disease.
  2. DNA samples from patients (cases) were analyzed for pathogenic point mutations in a number of PD linked genes e.g. LRRK2, PARKIN, PINK1, SNCA, DJ1 and others.
  3. Genetic analysis was carried out by means of Sanger sequencing.
  4. Mutation negative cases were then analyzed for changes in gene expression and in gene copy number.

 

Results

Ø  A total of 118 different genetic variants were discovered 18 of which are reported for the first time.

Ø  None of the study cases carried pathogenic mutations in the screened PD-known genes, except for three.

Ø  The identified mutations were found in genes linked with the autosomal recessive form of PD (PINK1 and PARKIN)

Ø  Two of the detected mutations are novel, a nonsense mutation in  PARKIN and the other is a missense  mutation in PINK1 that is predicted to alter the protein function.

Ø  Gene expression analysis of a subset of samples did not reveal any abnormal changes, however, copy number analysis detected a number of deletions in PARKIN in two patients.

 

Conclusion and Significance

Ø  Genetic studies of PD from Arab populations are scarce if not entirely lacking.

Ø  This study sheds light on the genetic basis of the second most common. neurodegenerative disorder in a cohort of 98 Saudi PD patients.

Ø  Mutations in PD common genes are under-represented in Saudi patients, which may point towards the involvement of new genes.

Ø  The remaining mutation-negative samples are being interrogated by means of whole-exome sequencing in an ongoing study.

Ø  Better understanding of the disease can improve diagnostic and therapeutic strategies.

 

 

Figure 1Figure 1. A schematic diagram summarizing the design and main findings of the study. Genetic mutations are indicated by the “X” symbol. Boxes highlighted in yellow denote deleted exons.

 

Glossary

Monogenic: resulting from defects in a single gene.

Familial: hereditary form in which the patient has first or second-degree relative with the same disease.

Sporadic: no family history of the disease.

Pathogenic point mutations: single-base genetic changes likely to disrupt gene function.

Sanger sequencing: a standard technique for reading genetic information.

Gene expression: how much of the genetic code is converted into protein producing instructions.

Genetic variants: changes in the DNA sequence.

Autosomal recessive disease: mutation has to be present in both copies of the gene to produce the disease.

Nonsense mutation: a mutation that introduces a stop codon predicted to result in a shorter dysfunctional version of the protein.

Missense mutation:  a mutation that alters the genetic codon and results in amino acid substitution.

 

References

  1. al Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, al-Freihi H, Assuhaimi S, Borollosi M, al-Shammasi S: A community survey of neurological disorders in Saudi Arabia: the Thugbah study. Neuroepidemiology 1993, 12(3):164-178.
  2. Fineberg NA, Haddad PM, Carpenter L, Gannon B, Sharpe R, Young AH, Joyce E, Rowe J, Wellsted D, Nutt DJ et al: The size, burden and cost of disorders of the brain in the UK. Journal of psychopharmacology (Oxford, England) 2013, 27(9):761-770.
  3. Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A: The current and projected economic burden of Parkinson’s disease in the United States. Movement disorders : official journal of the Movement Disorder Society 2013, 28(3):311-318.

 

Contact:

Bashayer Al Mubarak, PhD

Postdoctoral research fellow

Behavioural genetics Unit

Department of Genetics, Research Centre

King Faisal Specialist Hospital and Research Center

P.O. Box 3354 Riyadh 11211 Saudi Arabia

MBC -03-06

Tel: +966(1)4647272 Ext: 77695

Fax: +966(1)4424585

 

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