Alport syndrome causes: Difference between revisions

	Alport syndrome Microchapters
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Alport syndrome from other Diseases
Epidemiology and Demographics
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
Echocardiography or Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Alport syndrome causes On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Alport syndrome causes All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Alport syndrome causes
CDC on Alport syndrome causes
Alport syndrome causes in the news
Blogs on Alport syndrome causes
Directions to Hospitals Treating Alport syndrome
Risk calculators and risk factors for Alport syndrome causes

VisualWikitext

Revision as of 16:18, 31 October 2013

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

Overview

Causes

Genetics

         Normal  0          false  false  false    EN-US  JA  X-NONE

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.

References

↑ ^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.
↑ Gehrs KM, Pollock SC, Zilkha G (1995). "Clinical features and pathogenesis of Alport retinopathy". Retina. 15 (4): 305–11. PMID 8545576.
↑ ^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.
↑ ^4.0 ^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.
↑ ^5.0 ^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.
↑ ^6.0 ^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.
↑ Turco AE, Rossetti S, Bresin E, Corrá S (1995). "Erroneous genetic risk assessment of Alport syndrome". Lancet. 346 (8984): 1237. PMID 7475699.
↑ ^8.0 ^8.1 ^8.2 Flinter F (1993). "Molecular genetics of Alport's syndrome". Q J Med. 86 (5): 289–92. PMID 8327646.
↑ 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.
↑ McCarthy PA, Maino DM (2000). "Alport syndrome: a review". Clin Eye Vis Care. 12 (3–4): 139–150. PMID 11137428.
↑ 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.
↑ 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.
↑ Kashtan CE, Michael AF (1993). "Alport syndrome: from bedside to genome to bedside". Am J Kidney Dis. 22 (5): 627–40. PMID 8238007.
↑ Rumpelt HJ (1987). "Alport's syndrome: specificity and pathogenesis of glomerular basement membrane alterations". Pediatr Nephrol. 1 (3): 422–7. PMID 3153312.
↑ ^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.

Template:WH Template:WS

[pmid8154501-1] 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.

[pmid8545576-2] Gehrs KM, Pollock SC, Zilkha G (1995). "Clinical features and pathogenesis of Alport retinopathy". Retina. 15 (4): 305–11. PMID 8545576.

[pmid8178947-3] 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.

[pmid1689491-4] 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.

[pmid8414149-5] 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.

[pmid8253711-6] 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.

[pmid7475699-7] Turco AE, Rossetti S, Bresin E, Corrá S (1995). "Erroneous genetic risk assessment of Alport syndrome". Lancet. 346 (8984): 1237. PMID 7475699.

[pmid8327646-8] 8.0 ^8.1 ^8.2 Flinter F (1993). "Molecular genetics of Alport's syndrome". Q J Med. 86 (5): 289–92. PMID 8327646.

[pmid8414153-9] 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.

[pmid11137428-10] McCarthy PA, Maino DM (2000). "Alport syndrome: a review". Clin Eye Vis Care. 12 (3–4): 139–150. PMID 11137428.

[pmid2349482-11] 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.

[pmid7987396-12] 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.

[pmid8238007-13] Kashtan CE, Michael AF (1993). "Alport syndrome: from bedside to genome to bedside". Am J Kidney Dis. 22 (5): 627–40. PMID 8238007.

[pmid3153312-14] Rumpelt HJ (1987). "Alport's syndrome: specificity and pathogenesis of glomerular basement membrane alterations". Pediatr Nephrol. 1 (3): 422–7. PMID 3153312.

[pmid8176894-15] 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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

@@ Line 6: / Line 6: @@
 ==Causes==
 ===Genetics===
-Alport syndrome is caused by [[mutation]]s in the ''[[COL4A3]]'', ''[[COL4A4]]'', and ''[[COL4A5]]'' [[collagen]] biosynthesis genes.  Mutations in any of these genes prevent the proper production or assembly of the [[type IV collagen]] network, which is an important structural component of the [[glomerular basement membrane]]s in the [[kidney]], inner [[ear]], and [[eye]].
+          Normal  0          false  false  false    EN-US  JA  X-NONE
-This syndrome can have different inheritance patterns depending on the type of genetic mutation.  In most people with the disorder, the condition is inherited in an [[X-linked]] pattern due to mutations in the ''[[COL4A5]]'' gene.  A condition is considered X-linked if the gene involved in the disorder is located on the [[X chromosome]].
+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.<ref name="pmid8154501">{{cite journal| author=Bodziak KA, Hammond WS, Molitoris BA| title=Inherited diseases of the glomerular basement membrane. | journal=Am J Kidney Dis | year= 1994 | volume= 23 | issue= 4 | pages= 605-18 | pmid=8154501 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8154501 }} </ref>
-Alport syndrome can also be inherited in an [[autosomal recessive]] pattern if both copies of the ''COL4A3'' or ''COL4A4'' gene, located on [[chromosome 2 (human)|chromosome 2]], have been mutated.  Most often, the parents of a child with an autosomal recessive disorder are not affected but are only carriers of one copy of the altered genes.
+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.<ref name="pmid8545576">{{cite journal| author=Gehrs KM, Pollock SC, Zilkha G| title=Clinical features and pathogenesis of Alport retinopathy. | journal=Retina | year= 1995 | volume= 15 | issue= 4 | pages= 305-11 | pmid=8545576 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8545576 }} </ref><ref name="pmid8178947">{{cite journal| author=Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y et al.| title=Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. | journal=Am J Pathol | year= 1994 | volume= 144 | issue= 5 | pages= 986-96 | pmid=8178947 | doi= | pmc=PMC1887361 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8178947 }} </ref><ref name="pmid1689491">{{cite journal| author=Hostikka SL, Eddy RL, Byers MG, Höyhtyä M, Shows TB, Tryggvason K| title=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. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 4 | pages= 1606-10 | pmid=1689491 | doi= | pmc=PMC53524 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1689491 }} </ref>
-In males, who have only one X chromosome, one altered copy of the ''COL4A5'' gene is sufficient to cause severe Alport syndrome.  This single X chromosome explains why most affected males eventually develop [[chronic kidney failure]].  In females, who have two X chromosomes, a mutation in one copy of the ''COL4A5'' gene usually results in blood in the urine, but most affected females do not develop kidney failure.
+It is notable to realize that most cases of Alport’s syndrome are caused by an X-linked dominant pattern of inheritance<ref name="pmid8154501">{{cite journal| author=Bodziak KA, Hammond WS, Molitoris BA| title=Inherited diseases of the glomerular basement membrane. |journal=Am J Kidney Dis | year= 1994 | volume= 23 | issue= 4 | pages= 605-18 |pmid=8154501 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8154501 }} </ref><ref name="pmid8414149">{{cite journal| author=Knebelmann B, Antignac C, Gubler MC, Grünfeld JP| title=Molecular genetics of Alport syndrome: the clinical consequences. | journal=Nephrol Dial Transplant | year= 1993 | volume= 8 | issue= 8 | pages= 677-9 | pmid=8414149 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8414149 }} </ref> vs. only 15% of cases are due to autosomal inheritance.<ref name="pmid8154501">{{cite journal|author=Bodziak KA, Hammond WS, Molitoris BA| title=Inherited diseases of the glomerular basement membrane. |journal=Am J Kidney Dis | year= 1994 | volume= 23 |issue= 4 | pages= 605-18 |pmid=8154501 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8154501 }} </ref><ref name="pmid8414149">{{cite journal| author=Knebelmann B, Antignac C, Gubler MC, Grünfeld JP| title=Molecular genetics of Alport syndrome: the clinical consequences. |journal=Nephrol Dial Transplant | year= 1993 | volume= 8 | issue= 8 | pages= 677-9 |pmid=8414149 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8414149 }} </ref><ref name="pmid8253711">{{cite journal| author=Hudson BG, Reeders ST, Tryggvason K| title=Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. | journal=J Biol Chem | year= 1993 | volume= 268 | issue= 35 | pages= 26033-6 | pmid=8253711 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8253711 }} </ref> 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.<ref name="pmid7475699">{{cite journal| author=Turco AE, Rossetti S, Bresin E, Corrá S| title=Erroneous genetic risk assessment of Alport syndrome. | journal=Lancet | year= 1995 | volume= 346 | issue= 8984 | pages= 1237 | pmid=7475699 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7475699 }} </ref> 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.<ref name="pmid8327646">{{cite journal| author=Flinter F| title=Molecular genetics of Alport's syndrome. | journal=Q J Med | year= 1993 | volume= 86 | issue= 5 | pages= 289-92 | pmid=8327646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8327646 }} </ref><ref name="pmid8414153">{{cite journal| author=Chugh KS, Sakhuja V, Agarwal A, Jha V, Joshi K, Datta BN et al.| title=Hereditary nephritis (Alport's syndrome)--clinical profile and inheritance in 28 kindreds. | journal=Nephrol Dial Transplant | year= 1993 | volume= 8 | issue= 8 | pages= 690-5 | pmid=8414153 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8414153 }} </ref><ref name="pmid11137428">{{cite journal| author=McCarthy PA, Maino DM| title=Alport syndrome: a review. | journal=Clin Eye Vis Care | year= 2000 | volume= 12 | issue= 3-4 | pages= 139-150 | pmid=11137428 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11137428 }} </ref> 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.<ref name="pmid2349482">{{cite journal| author=Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC et al.| title=Identification of mutations in the COL4A5 collagen gene in Alport syndrome. | journal=Science | year= 1990 | volume= 248 | issue= 4960 | pages= 1224-7 | pmid=2349482 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2349482 }} </ref><ref name="pmid7987396">{{cite journal| author=Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y et al.| title=Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. | journal=Nat Genet | year= 1994 | volume= 8 | issue= 1 | pages= 77-81 | pmid=7987396 | doi=10.1038/ng0994-77 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7987396 }} </ref>
+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.<ref name="pmid8253711">{{cite journal| author=Hudson BG, Reeders ST, Tryggvason K| title=Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. | journal=J Biol Chem | year= 1993 | volume= 268 | issue= 35 | pages= 26033-6 | pmid=8253711 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8253711 }} </ref><ref name="pmid8238007">{{cite journal| author=Kashtan CE, Michael AF| title=Alport syndrome: from bedside to genome to bedside. | journal=Am J Kidney Dis | year= 1993 | volume= 22 | issue= 5 | pages= 627-40 | pmid=8238007 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8238007 }} </ref><ref name="pmid3153312">{{cite journal| author=Rumpelt HJ| title=Alport's syndrome: specificity and pathogenesis of glomerular basement membrane alterations. | journal=Pediatr Nephrol | year= 1987 | volume= 1 | issue= 3 | pages= 422-7 | pmid=3153312 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3153312 }} </ref><ref name="pmid8176894">{{cite journal| author=Cheong HI, Kashtan CE, Kim Y, Kleppel MM, Michael AF| title=Immunohistologic studies of type IV collagen in anterior lens capsules of patients with Alport syndrome. | journal=Lab Invest | year= 1994 | volume= 70 | issue= 4 | pages= 553-7 | pmid=8176894 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8176894 }} </ref>
+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.<ref name="pmid8178947">{{cite journal| author=Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y et al.| title=Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. | journal=Am J Pathol | year= 1994 | volume= 144 | issue= 5 | pages= 986-96 | pmid=8178947 | doi= | pmc=PMC1887361 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8178947 }} </ref><ref name="pmid1689491">{{cite journal| author=Hostikka SL, Eddy RL, Byers MG, Höyhtyä M, Shows TB, Tryggvason K| title=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. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 4 | pages= 1606-10 | pmid=1689491 | doi= | pmc=PMC53524 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1689491 }} </ref> Common mutations that are involved in Alport’s syndrome are cysteine to serine point mutations<ref name="pmid8327646">{{cite journal| author=Flinter F| title=Molecular genetics of Alport's syndrome. | journal=Q J Med | year= 1993 | volume= 86 | issue= 5 | pages= 289-92 | pmid=8327646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8327646 }} </ref>, glycine substitutions<ref name="pmid8253711">{{cite journal| author=Hudson BG, Reeders ST, Tryggvason K| title=Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. | journal=J Biol Chem | year= 1993 | volume= 268 | issue= 35 | pages= 26033-6 | pmid=8253711 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8253711 }} </ref>, and mutations of NC1 domains that affect intermolecular interactions<ref name="pmid8253711">{{cite journal| author=Hudson BG, Reeders ST, Tryggvason K| title=Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. | journal=J Biol Chem | year= 1993 | volume= 268 | issue= 35 | pages= 26033-6 | pmid=8253711 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8253711 }} </ref>.
+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<ref name="pmid8327646">{{cite journal| author=Flinter F| title=Molecular genetics of Alport's syndrome. | journal=Q J Med | year= 1993 | volume= 86 | issue= 5 | pages= 289-92 | pmid=8327646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8327646 }} </ref><ref name="pmid8176894">{{cite journal| author=Cheong HI, Kashtan CE, Kim Y, Kleppel MM, Michael AF| title=Immunohistologic studies of type IV collagen in anterior lens capsules of patients with Alport syndrome. | journal=Lab Invest | year= 1994 | volume= 70 | issue= 4 | pages= 553-7 | pmid=8176894 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8176894 }} </ref><ref name="pmid8253711">{{cite journal| author=Hudson BG, Reeders ST, Tryggvason K| title=Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. | journal=J Biol Chem | year= 1993 | volume= 268 | issue= 35 | pages= 26033-6 | pmid=8253711 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8253711 }} </ref>, but the association of male gender with severity has been well verified since the very first description of the disease by AC Alport himself.
 ==References==