Alport syndrome causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]




Alport’s syndrome (AC) or hereditary nephritis is a familial nephropathy caused by a genetic defect in the alpha-5 chains of type IV collagen, which comprises approximately 50% of the basement membrane and is responsible for its plasticity and strength.[1]

In 1990, Barker and colleagues discovered that Alport’s syndrome is caused by a defect of the COL4A5 gene on the long arm of the X chromosome located at Xq22-23 region. It normally codes for alpha-5 chains that have been found to be defective in Alport’s syndrome.[2][3][4] It is notable to realize that most cases of Alport’s syndrome are caused by an X-linked dominant pattern of inheritance[1][5] vs. only 15% of cases are due to autosomal inheritance.[1][5][6] Autosomal recessive inheritance most likely is not caused by a defect of alpha-5 chains, but rather a defect of alpha-3 and alpha-4 chains of type IV collagen on chromosome 2.[7] On the other hand, autosomal dominant pattern of inheritance is presumable in cases of reduced severity; it is due to heterozygous COL4A3 or COL4A4 mutations.[8][9][10] To sum up, more than 85% of patients with Alport’s syndrome have a mutation of COL4A5 gene, leading to an X-linked Alport’s syndrome. Less common mutations that cause Alport’s syndrome are due to COL4A3 and COL4A4 genes mutations that cause the autosomal recessive type of Alport’s syndrome.[11][12]

Alpha-5 chains are responsible for giving solidity in the final step of collagen synthesis. Thus, a defect of the alpha-5 chains is likely to cause a defect of all 3 intertwined collagen chains and affecting the entire collagen product.[6][13][14][15]

The exact type of defect is difficult to characterize; there are at least 40 mutations that have been already described in Alport’s syndrome; some of which involve insertion, point or multiple deletions, or genetic rearrangement.[3][4] Common mutations that are involved in Alport’s syndrome are cysteine to serine point mutations[8], glycine substitutions[6], and mutations of NC1 domains that affect intermolecular interactions[6]. There does not seem to be a clear correlation between the severity of symptoms in Alport’s syndrome and the amount or quality of genetic mutations. To date, the literature is still uncertain about obvious genetic and clinical associations[8][15][6], but the association of male gender with severity has been well verified since the very first description of the disease by AC Alport himself.[16]


Phenotypic expressions of Alport’s syndrome differ from one patient to another. They have become the basis for classification of Alport’s syndrome, according to Atkin and colleagues in 1993.[9][10]

According to Atkin and colleagues, the main classification differentiates adult vs. juvenile Alport’s syndrome. The classification is based on time to reach end-stage renal disease (ESRD), mode of inheritance, and presence of ocular and auditory anomalies.[9][10]

  • Adult: XD inheritance and time to reach ESRD is generally after 31 years of age. Its extra-renal manifestations are typically less commonly seen compared to its juvenile counterpart. In adult subtype, only 50% of patients have auditory anomalies, whereas visual defects are almost never seen.[9][10]
  • Juvenile: XD or autosomal mode of inheritance. Patients rapidly reach ESRD before 31 years of age. Almost all patients have auditory deficient and ocular manifestations are generally present.[9][10]

However, Atkin and colleagues[9][10],further classified Alport’s syndrome into 6 types from I-VI with 6 characteristics to differentiate various subtypes: The characteristics are not exclusive to different subtypes; some of which may be present or absent within the same subtype.

  • Inheritance: XD for I, II, III, IV vs. AD for I, V, VI
  • Adult vs. juvenile: Adult: III, IV, V vs. juvenile I, II, V, VI
  • Presence of auditory deficit: I, II, V, VI
  • Presence of ocular anomalies: I, II, VI
  • Presence of subtypes: III and VI
  • Presence of AS variant, such as Epstein syndrome: V

According to this classification, types I and VI only differ by the inability of the former to produce offspring, compared to the normal ability to reproduce in the latter.[9][10] Otherwise, all 6 characteristics are generally similar in both subtypes.


  1. 1.0 1.1 1.2 Bodziak KA, Hammond WS, Molitoris BA (1994). "Inherited diseases of the glomerular basement membrane". Am J Kidney Dis. 23 (4): 605–18. PMID 8154501.
  2. Gehrs KM, Pollock SC, Zilkha G (1995). "Clinical features and pathogenesis of Alport retinopathy". Retina. 15 (4): 305–11. PMID 8545576.
  3. 3.0 3.1 Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y; et al. (1994). "Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody". Am J Pathol. 144 (5): 986–96. PMC 1887361. PMID 8178947.
  4. 4.0 4.1 Hostikka SL, Eddy RL, Byers MG, Höyhtyä M, Shows TB, Tryggvason K (1990). "Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome". Proc Natl Acad Sci U S A. 87 (4): 1606–10. PMC 53524. PMID 1689491.
  5. 5.0 5.1 Knebelmann B, Antignac C, Gubler MC, Grünfeld JP (1993). "Molecular genetics of Alport syndrome: the clinical consequences". Nephrol Dial Transplant. 8 (8): 677–9. PMID 8414149.
  6. 6.0 6.1 6.2 6.3 6.4 Hudson BG, Reeders ST, Tryggvason K (1993). "Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis". J Biol Chem. 268 (35): 26033–6. PMID 8253711.
  7. Turco AE, Rossetti S, Bresin E, Corrá S (1995). "Erroneous genetic risk assessment of Alport syndrome". Lancet. 346 (8984): 1237. PMID 7475699.
  8. 8.0 8.1 8.2 Flinter F (1993). "Molecular genetics of Alport's syndrome". Q J Med. 86 (5): 289–92. PMID 8327646.
  9. 9.0 9.1 9.2 9.3 9.4 9.5 9.6 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.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 McCarthy PA, Maino DM (2000). "Alport syndrome: a review". Clin Eye Vis Care. 12 (3–4): 139–150. PMID 11137428.
  11. 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.
  12. Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y; et al. (1994). "Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome". Nat Genet. 8 (1): 77–81. doi:10.1038/ng0994-77. PMID 7987396.
  13. Kashtan CE, Michael AF (1993). "Alport syndrome: from bedside to genome to bedside". Am J Kidney Dis. 22 (5): 627–40. PMID 8238007.
  14. Rumpelt HJ (1987). "Alport's syndrome: specificity and pathogenesis of glomerular basement membrane alterations". Pediatr Nephrol. 1 (3): 422–7. PMID 3153312.
  15. 15.0 15.1 Cheong HI, Kashtan CE, Kim Y, Kleppel MM, Michael AF (1994). "Immunohistologic studies of type IV collagen in anterior lens capsules of patients with Alport syndrome". Lab Invest. 70 (4): 553–7. PMID 8176894.
  16. Alport AC (1927). "HEREDITARY FAMILIAL CONGENITAL HAEMORRHAGIC NEPHRITIS". Br Med J. 1 (3454): 504–6. PMC 2454341. PMID 20773074.

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