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1. Introduction
2. The carbonic anhydrase (CA) reaction
3. The first known inherited CA deficiency syndrome
4. First feature: bone fracture and osteopetrosis
5. The reasons for suspecting it was a new disease
6. Second feature: renal tubular acidosis (RTA)
7. Third feature: cerebral calcification
8. What enzyme deficiency produce such defects?
9. Patterns of erythrocyte CA I and CA II
10. My first paper on carbonic anhydrases
11. Osteopetrosis/RTA always true for CA II-deficiency
12. 16 structural gene mutations in CA II-deficiency
13. The proposed roles of CA II and CA IV
14. How do we explain cerebral calcification?
15. 1983: 50-year anniversary symposium
16. How was carbonic anhydrase discovered?
17. Purified enzyme was found to contain zinc
18. 1945 - 1960: the middle years
19. 1960 - 1980: the protein era
20. Other CA family members known by 1983
21. Why six enzymes for such a simple reaction?
22. Partial answer: compartmentalization
23. 260-amino acid CA domain is common to all CAs
24. N-terminal a.a sequences of catalytic human CAs
25. C-terminal a.a sequences of catalytic human CAs
26. CA-related proteins (CARPs)
27. Why was CA IV of special interest?
28. CA IV in the lumen of the proximal renal tubules
29. Immunofluorescent labeling of CA IV
30. Cartoon of the CA IV-membrane interaction
31. Back to the American family with CA II-deficiency
32. What CA IV does in your proximal tubules
33. How to prove it? find a CA IV deficient patient
34. On to the mouse!
35. Mouse knockout has no kidney phenotype
36. CA IV and CA XIV in kidney proximal tubules
37. Wrong predicted CA IV deficiency phenotype
38. Summary of CA IV and CA XIV findings in kidney
39. Confocal laser scanning images of CA XIV
40. CA XIV enrichment in specific membrane domains
41. CA XIV is the membrane CA in the retina
42. CA IV and XIV knockout mice
43. We thought we were finished with CA IV...
44. South African family with retinitis pigmentosa
45. What is retinitis pigmentosa (RP)?
46. What does the retina look like in RP?
47. Rhodopsin mutations and retinal disorders
48. Predicted R14W mutation effect on CA IV protein
49. Could we find a precedent?
50. CA IV is absent in the retina
51. CA IV is highly expressed in the choriocapillaris
52. A working hypothesis for RP17
53. What is the UPR?
54. How does the UPR help the cell handle ER stress
55. R14W mutant CA expression in COS-7 cells
56. R14W mutation reduces-steady state level
57. Turnover of R14W and wild-type CA IV protein
58. R14W mutation and induction of ER proteins
59. R14W CA IV-induced ER stress and apoptosis
60. R14W CA IV induces upregulation of CHOP
61. R14W CA IV induces Annexin V / TUNEL staining
62. Apoptosis-inducing signal sequence in CA IV
63. So what? good question!
64. If RP17 is a protein folding disease...
65. Acetazolamide and R14W CA IV degradation rate
66. PBA and R14W CA IV biosynthesis and stability
67. Will CA inhibitors reduce UPR gene upregulation?
68. Chemical chaperones and apoptosis protection
69. Summary
70. Future studies
71. Immunofluorescence of transgenic retina
72. TUNEL staining of retina from control mouse
73. R14W CA IV transgenic mouse retina staining

Topics Covered

• Carbonic anhydrase deficiencies
• History of the disease
• Roles of CA II and IV in disease
• Sulfonamide inhibitors for treatment of some disorders
• Characterization of CA isozymes
• CA IV discovery and function
• Mouse knockout models of CA deficiencies
• CA IV, unfolded protein response and retinitis pigmentosa
• ER stress and apoptosis in the choriocapillaris
• Chemical chaperones and treatment of retinitis pigmentosa
• Future studies

Links

Series:

• Protein Epidemiology

Categories:

• Biochemistry
• Cell Biology
• Clinical Practice
• Genetics & Epigenetics

Therapeutic Areas:

• Gastroenterology & Nephrology

Talk Citation

Publication History

• Published on October 1, 2007
• Archived on February 25, 2021

Financial Disclosures

• Prof. William Sly has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.