Alport syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3]
Overview
Pathogenesis
Alport Syndrome occurs due to a mutation in the α-3, α-4, α-5 chains. These chains are essential in forming the basement membrane. The mutations of these chains are caused by a gene mutation in COL4A5 that encodes the alpha-5 chain on the X-chromosome . A gene mutation of COL4A3 that encodes the alpha-3 chain and COL4A4 that affects the alpha-4 chain. [1]
A mutation in any of these genes results in misfolded polypeptides and improperly assembled proteins. This is due to mRNA being misread by the ribosomes. The improper reading of mRNA leads to α-3,α-4,α-5 chains to be shutdown. The shutdown of these chains results in immature development of the glomerular basement membrane, as α-3,α-4,α-5 chains are essential in producing a mature and well functioning glomerular basement membrane. When these chains are shutdown, embryonic developmental chains (α-1.,α-1., α-2.) are still being produced in the glomerular basement membrane. The production of only these chains in the glomerular basement membrane results in the glomerular basement membrane to be prone to endoproteolysis and oxidative stressors. As time progresses, the renal under constant oxidative stressors and endoproteolysis conforms the glomerular basement membrane to become unevenly thick, split, and unfortunately damaged in a way that it is no longer able to function properly.[2]
Genetics
Alport syndrome is a rare inherited disease, that is passed down by the mother's or father's X chromosome or a mutation involving chromosome 2. There are three forms of inheritance. It can either be x-linked, autosomal dominant, or autosomal recessive.[3]
Microscopic Pathology
Alport’s syndrome is characterized by the defect of alpha chains of type IV collagen that constitute a triad of manifestations: renal, auditory, and ocular. Involvement of the glomerular basement membrane is the hallmark of Alport’s syndrome.[5][6] It is still controversial as to whether the basement membrane becomes thicker or thinner to induce splitting.
| Manifestations | Renal | Auditory | Ocular |
| Molecular Findings | Absence of collagen network of the glomerular basement membrane (GBM) that is normally formed by podocytes and endothelial cells[7][8][9] | Cellular loss, including hair cells of Corti, and edema associated with atrophy of tissue[10][11][12][13] | Cellular loss and mitochondrial edema. Honeycombing of broken abnormal filaments that are surrounded by vacuolated spheres and membranes[14][11] |
| Histopathological Changes | Lamellated GBM and splitting with appearance of false layers of the basement membrane leading to focal sclerosis of glomeruli[10][11][12][5] | Basement changes of the stria vascularis of the cochlea | Pathological changes involving the lens capsule, the largest basement membrane in the eye[14][11] |
Alpha chains of type IV collagen are located at specific regions in the body. However, the involvement of one type of alpha chain does not necessarily have to involve all corresponding beds that are known to be composed of that same collagen type. To date, there has been no valid hypothesis of why renal, auditory, and ocular manifestations are observed in Alport’s syndrome, but other basement membrane beds involving alpha-5 type IV collagen are no involved, such as the epidermal basement membrane of the skin.[11][15]
References
- ↑ Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG (2003). "Alport's syndrome, Goodpasture's syndrome, and type IV collagen". N Engl J Med. 348 (25): 2543–56. doi:10.1056/NEJMra022296. PMID 12815141.
- ↑ Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG (2003). "Alport's syndrome, Goodpasture's syndrome, and type IV collagen". N Engl J Med. 348 (25): 2543–56. doi:10.1056/NEJMra022296. PMID 12815141.
- ↑ Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F (2013). "Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy". J Am Soc Nephrol. 24 (3): 364–75. doi:10.1681/ASN.2012020148. PMID 23349312.
- ↑ 4.0 4.1 4.2 4.3 Alport Syndrome Foundation. www.alportsyndrome.org/alport-syndrome/alport-syndrome-genetics/ Accessed on November 2, 2016
- ↑ 5.0 5.1 Bodziak KA, Hammond WS, Molitoris BA (1994). "Inherited diseases of the glomerular basement membrane". Am J Kidney Dis. 23 (4): 605–18. PMID 8154501.
- ↑ Kashtan CE, Michael AF (1993). "Alport syndrome: from bedside to genome to bedside". Am J Kidney Dis. 22 (5): 627–40. PMID 8238007.
- ↑ Abrahamson DR, Hudson BG, Stroganova L, Borza DB, St John PL (2009). "Cellular origins of type IV collagen networks in developing glomeruli". J Am Soc Nephrol. 20 (7): 1471–9. doi:10 .1681/ASN.2008101086 Check
|doi=value (help). PMC 2709682. PMID 19423686. - ↑ Miner JH (1998). "Developmental biology of glomerular basement membrane components". Curr Opin Nephrol Hypertens. 7 (1): 13–9. PMID 9442357.
- ↑ St John PL, Abrahamson DR (2001). "Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and -11 chains". Kidney Int. 60 (3): 1037–46. doi:10.1046/j.1523-1755.2001.0600031037.x. PMID 11532098.
- ↑ 10.0 10.1 Chugh KS, Sakhuja V, Agarwal A, Jha V, Joshi K, Datta BN; et al. (1993). "Hereditary nephritis (Alport's syndrome)--clinical profile and inheritance in 28 kindreds". Nephrol Dial Transplant. 8 (8): 690–5. PMID 8414153.
- ↑ 11.0 11.1 11.2 11.3 11.4 McCarthy PA, Maino DM (2000). "Alport syndrome: a review". Clin Eye Vis Care. 12 (3–4): 139–150. PMID 11137428.
- ↑ 12.0 12.1 Andreoli SP, Deaton M (1992). "Alport's syndrome". Ear Nose Throat J. 71 (10): 508–11. PMID 1425373.
- ↑ Grondalski SJ, Bennett GR (1989). "Alport's syndrome: review and case report". Optom Vis Sci. 66 (6): 396–8. PMID 2771325.
- ↑ 14.0 14.1 Streeten BW, Robinson MR, Wallace R, Jones DB (1987). "Lens capsule abnormalities in Alport's syndrome". Arch Ophthalmol. 105 (12): 1693–7. PMID 3689194.
- ↑ Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC; et al. (1990). "Identification of mutations in the COL4A5 collagen gene in Alport syndrome". Science. 248 (4960): 1224–7. PMID 2349482.