ALU-INSERTION Yb8NBC36 IN THE KCNJ6 GENE IS A RISK FACTOR FOR PARKINSON’S DISEASE
Gilyazova I1,*, Khidiyatova I1, Akhmetova V1, Baitimerov A2, Magzhanov R2, Khusnutdinova E1
*Corresponding Author: Dr. Irina Gilyazova, Department of Human Genomics, Institute of Biochemistry and Genetics, Ufa Science Center, Russian Academy of Sciences, 71 Prospekt Oktyabrya, Ufa 450054, Russia; Tel.: +7(3472)356088; Fax: +7(3472)356100; E-mail: gilyasova_irina@mail.ru
page: 43

DISCUSSION

 

      Investigation of potassium channels in neurodegen­erative diseases is important because of their significant role in many physiological functions. Potassium channels are important in shaping the action potential, in neuron excitability and plasticity, and in eukaryotic cells, in neu­ral signaling and generation of the cardiac rhythm. The family of G-protein gated inwardly rectifying K+ channels is predominantly expressed in central neurons and neuro­endocrine cells [9], and may play an important role in the development of neurodegenerative diseases.

      A missence mutation (G156C) in the H5 region of the KCNJ6 gene was found to be the molecular defect in the weaver mouse [8]. Bandmann et al. [7], trying to evaluate the possibility of a shared genetic effect in weaver mice and PD, found no mutations in the pore region of the KCNJ6 gene in 50 cases of PD, 23 of which were index cases of familial PD. Goldowitz and Smeyne [6] described developmental events in the early postnatal cerebellum in wild type and weaver mouse, the expression pattern of KCNJ6 mRNA in the adult brain, and the proposed role of this gene in normal and abnormal cell differentiation. Guatteo et al. [16] have shown that the mutated KCNJ6 channel loses its potassium selectivity and allows Na+ and Ca2+ ions to enter the cell that leads to degeneration of cerebellar granule and midbrain dopaminergic neurons. They suggested that the susceptibility to cell death of wvKCNJ6-expressing dopaminergic neurons might be due to a wvKCNJ6-mediated depolarization evoked by D2 receptor and GABAB receptor activation [16,17]. How­ever, a detailed study of KCNJ6 channels is still lacking.

      The Alu-insertion Yb8NBC36 polymorphism of the KCNJ6 gene has not been studied before in PD patients. Insertion of an Alu-element may alter the transcription of a gene by changing the methylation status of its promoter, by disrupting its promoter or by introducing additional regulatory sequences, such as the binding sites for steroid-hormone receptors that are contained in some Alu-family members [18,19]. Alternatively, an Alu repeat could inte­grate directly into the coding region of a gene and disrupt the open reading frame, thus generating a nonsense or frameshift mutation, or disrupting the splicing of a gene. We propose that the Alu-insertion Yb8NBC36 may alter the KCNJ6 gene expression. We suggest that altered KCNJ6 gene expression may alter the function of the GIRK channel, leading to loss of potassium selectivity and ion flow alterations, i.e., entry of Na+ and Ca2+ ions in the cell that may result in degeneration of dopaminergic neu­rons, the main cause of PD development. Further investi­gations are required to understand the role of potassium inwardly-rectifying channel in pathogenesis of PD.

 

Table 2. Allele and genotype frequency distributions of Alu-insertion Yb8NBC36 locus in the KCNJ6 gene in Parkinson’s Disease patients with different forms, age at onset and severity, and in healthy controls from the Bashkortostan Republic.

 

 

Yb8NBC36

Alleles

Genotypes

 

N

χ2

(p)

OR

95% CI

OR

RR

95% CI

RR

 

 *I

 *D

*I/*I

*I/*D

 

 

 

 

 

 

PD Forms

n

p

n

p

n

p

n

p

 

 

 

 

 

 

A-T-R

20

90.91

2

9.09

9

81.82

2

18.18

11

7.44 (0.0070)

7.89

1.55-54.19

2.25

1.28-2.71

A-R

26

86.67

4

13.33

11

73.33

4

26.67

15

6.74 (0.0100)

4.83

1.37-18.54

2.02

1.20-2.58

A-R-T

145

84.3

27

15.7

59

68.6

27

31.4

86

26.02 (0.0005)

3.83

2.21-6.68

1.89

1.49-2.30

T-R

52

83.87

10

16.13

21

67.74

10

32.26

31

10.16 (0.0023)

3.69

1.57-8.80

1.87

1.28-2.38

R-T

56

82.35

12

17.65

22

64.71

12

35.29

34

8.99 (0.0036)

3.21

1.44-7.27

1.78

1.23-2.30

Total

299

84.46

55

15.54

122

68.93

55

31.07

177

–

–

–

–

–

Age of Onset

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Before 40

21

80.77

5

19.23

8

61.54

5

38.46

13

2.37 (0.12)

–

–

–

–

From 40-60

118

85.51

20

14.49

49

71.01

20

28.99

69

25.32 (0.0005)

4.3

2.33-8.00

1.96

1.53-2.38

Over 60

101

87.07

15

12.93

43

74.14

15

25.86

58

26.14 (0.0005)

5.03

2.55-10.05

2.04

1.59-2.46

Total

240

85.71

40

14.29

100

71.43

40

28.57

140

–

–

–

–

–

PD Severity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stage II

19

86.36

3

13.64

8

72.72

3

27.27

11

4.51 (0.03)

4.68

1.09-22.84

2

1.06-2.61

Stage III

79

84.04

15

15.96

32

68.09

15

31.91

47

15.31 (0.0007)

3.74

1.84-7.68

1.88

1.39-2.34

Stage IV

135

85.44

23

14.56

56

70.89

23

29.11

79

27.96 (0.0005)

4.27

2.39-7.67

1.95

1.55-2.36

Stage V

40

86.96

6

13.04

17

73.91

6

26.09

23

10.99 (0.0017)

4.97

1.77-14.66

2.04

1.37-2.54

Total

273

85.31

47

14.69

113

70.63

47

29.37

160

–

–

–

–

–

 

N: number of DNA examined; OR: odds ratio; 95% CI: 95% confidence interval; RR: relative risk; n: number of chromosomes; p: frequency (%). The χ 2, OR and RR are only given for the genotype of risk (*I/*I); the *D/*D genotype was not found in any patient or control. A-T-R: akinetic-trembling rigid; A-R: akinetic-rigid; A-R-T: akinetic-rigid-trembling; T-R: trembling-rigid; R-T: rigid-trembling.

 




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