Alport syndrome

[Cream Soda]

Would have asked in the random question thread, but if anyone can help with this, I need to know the answer by 12pm today.

Basically, I'm writing a paper on Alport syndrome and I have a good amount of content (only rough draft is due today), but one of the parameters is that the type of mutation needs to be listed. (point mutation, frameshift, etc.), which I'm not having any luck finding.

The only info I can find is that it's a mutation in alpha-3, alpha-4, or alpha-5 chains of collagen 4, but not the type of mutation it is.

If anyone just happens to know or has a better way of finding out than I do (because not working for me), it'd be much appreciated.

[myreality]

The site below should help you out a lot, there are dozens of links that get more specific on the disease.
http://ghr.nlm.nih.gov/condition/alport-syndrome

What is Alport syndrome?
Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.
People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD).
People with Alport syndrome frequently develop sensorineural hearing loss, which is caused by abnormalities of the inner ear, during late childhood or early adolescence. Affected individuals may also have misshapen lenses in the eyes (anterior lenticonus) and abnormal coloration of the light-sensitive tissue at the back of the eye (retina). These eye abnormalities seldom lead to vision loss.
Significant hearing loss, eye abnormalities, and progressive kidney disease are more common in males with Alport syndrome than in affected females.
How common is Alport syndrome?

Alport syndrome occurs in approximately 1 in 50,000 newborns.
What genes are related to Alport syndrome?
Mutations in the COL4A3, COL4A4, and COL4A5 genes cause Alport syndrome. These genes each provide instructions for making one component of a protein called type IV collagen. This protein plays an important role in the kidneys, specifically in structures called glomeruli. Glomeruli are clusters of specialized blood vessels that remove water and waste products from blood and create urine. Mutations in these genes result in abnormalities of the type IV collagen in glomeruli, which prevents the kidneys from properly filtering the blood and allows blood and protein to pass into the urine. Gradual scarring of the kidneys occurs, eventually leading to kidney failure in many people with Alport syndrome.
Type IV collagen is also an important component of inner ear structures, particularly the organ of Corti, that transform sound waves into nerve impulses for the brain. Alterations in type IV collagen often result in abnormal inner ear function, which can lead to hearing loss. In the eye, this protein is important for maintaining the shape of the lens and the normal color of the retina. Mutations that disrupt type IV collagen can result in misshapen lenses and an abnormally colored retina.

Read more about the COL4A3, COL4A4, and COL4A5 genes.
How do people inherit Alport syndrome?
Alport syndrome can have different inheritance patterns. About 80 percent of cases are caused by mutations in the COL4A5 gene and are inherited in an X-linked pattern. This gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the COL4A5 gene in each cell is sufficient to cause kidney failure and other severe symptoms of the disorder. In females (who have two X chromosomes), a mutation in one copy of the COL4A5 gene usually only results in hematuria, but some women experience more severe symptoms. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In approximately 15 percent of cases, Alport syndrome results from mutations in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the mutated gene and are called carriers. Some carriers are unaffected and others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria.

Alport syndrome has autosomal dominant inheritance in about 5 percent of cases. People with this form of Alport syndrome have one mutation in either the COL4A3 or COL4A4 gene in each cell. It remains unclear why some individuals with one mutation in the COL4A3 or COL4A4 gene have autosomal dominant Alport syndrome and others have thin basement membrane nephropathy.

Where can I find information about diagnosis or management of Alport syndrome?
These resources address the diagnosis or management of Alport syndrome and may include treatment providers.
Gene Review: Collagen IV-Related Nephropathies (Alport Syndrome and Thin Basement Membrane Nephropathy)
Gene Tests: COL4A3 Alport Syndrome and Thin Basement Membrane Nephropathy
Gene Tests: COL4A4 Alport Syndrome and Thin Basement Membrane Nephropathy
Gene Tests: COL4A5 Alport Syndrome
Genetic Alliance
MedlinePlus Encyclopedia: Alport syndrome
MedlinePlus Encyclopedia: End-stage kidney disease

You might also find information on the diagnosis or management of Alport syndrome in Educational resources and Patient support.
General information about the diagnosis and management of genetic conditions is available in the Handbook.
To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about Alport syndrome?
You may find the following resources about Alport syndrome helpful. These materials are written for the general public.
MedlinePlus - Health information (4 links)
Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases (3 links)
Additional NIH Resources - National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases
Educational resources - Information pages (4 links)
Patient support - For patients and families (3 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.
Gene Reviews - Clinical summary
Gene Tests - Genetic tests ordered by healthcare professionals (3 links)
ClinicalTrials.gov - Linking patients to medical research
PubMed - Recent literature
OMIM - Genetic disorder catalog (3 links)
What other names do people use for Alport syndrome?
congenital hereditary hematuria
hematuria-nephropathy-deafness syndrome
hematuric hereditary nephritis
hemorrhagic familial nephritis
hemorrhagic hereditary nephritis
hereditary familial congenital hemorrhagic nephritis
hereditary hematuria syndrome
hereditary interstitial pyelonephritis
Hereditary nephritis

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about Alport syndrome?
Ask the Genetic and Rare Diseases Information Center.
Where can I find general information about genetic conditions?
The Handbook provides basic information about genetics in clear language.
What does it mean if a disorder seems to run in my family?
What are the different ways in which a genetic condition can be inherited?
If a genetic disorder runs in my family, what are the chances that my children will have the condition?
Why are some genetic conditions more common in particular ethnic groups?
These links provide additional genetics resources that may be useful.
Genetics and health
Resources for Patients and Families
Resources for Health Professionals
What glossary definitions help with understanding Alport syndrome?
anterior ; autosomal ; autosomal dominant ; autosomal recessive ; carrier ; cell ; chromosome ; chronic ; collagen ; congenital ; end-stage renal disease ; ESRD ; familial ; gene ; glomerulus ; hematuria ; inheritance ; inheritance pattern ; kidney ; mutation ; nephritis ; nephropathy ; protein ; proteinuria ; recessive ; renal ; renal disease ; retina ; sensorineural ; sensorineural hearing loss ; sex chromosomes ; stage ; symptom ; syndrome ; tissue ; trait
You may find definitions for these and many other terms in the Genetics Home Reference Glossary.
See also Understanding Medical Terminology.
References (12 links)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

[Silenka]

http://www.ncbi.nlm.nih.gov/pubmed/8225325

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915065/

http://science.civicvoice.com/q4831_...g_infants.html

It's looking like frameshift is the one that comes up most often. I just searched Alport syndrome + frameshift though.

[Cream Soda]

That should be good enough, at least for now. Only the rough draft is due today. I can go back and make adjustments later.

Thanks a bunch for the previous two posts. Will help a ton

[myreality]

Yup, Good luck.

[Daemien]

Alport’s syndrome is caused by mutations in genes encoding α-chains of type IV collagen that forms the structural skeleton of basement membranes. Type IV collagen molecules are large triple-helical proteins containing three α-chains. There exist six genetically distinct α-chains that in vivo are present in three trimeric isoforms: α1:α1:α2, α3:α4:α5, and α5:α5:α6.[65] The α1:α1:α2 trimer, a ubiquitous isoform present in basement membranes of most tissues, is expressed in the GBM during embryogenesis, but after birth it is replaced by an adult isoform, α3:α4:α5, that is a more stable protein containing more cross-links and that is more resistant to proteinases.[66] The α3-, α4-, and α5-chains are encoded by the COL4A3, COL4A4, and COL4A5 genes, respectively. COL4A5 is located head-to-head with COL4A6 on the X chromosome, and COL4A3 and COL4A4 are located head-to-head on chromosome 2 (see Figure 43-1).[66] As a consequence of either structurally abnormal α3:α4:α5 collagen molecules or their absence, the GBM structural framework becomes distorted and regionally broken down, which, in turn, allows for limited passage of red blood corpuscles into the urine.

Male patients with X-linked Alport’s syndrome are hemizygous for mutations in a single allele of the COL4A5 gene.[9] Several hundred mutations, including missense and nonsense (frameshift) mutations, splice mutations, deletions, insertions, and inversions have been described, and new mutations are continuously identified.[10,99,110,145] On occasion, concomitant mutations in the adjacent COL4A6 gene can additionally result in leiomyomatosis.[3] Heterozygous female carriers usually exhibit hematuria, but in most cases it is not progressive, and they rarely develop end-stage renal disease.[47]

Autosomal recessive Alport’s syndrome is caused by compound heterozygous or homozygous mutations in the COL4A3 and COL4A4 genes that are located on chromosome 2q.[5,92,95,106,162] Single-allele mutations do not result in real Alport’s syndrome, but they are associated with TBMN (see later discussion).

Data are strongly suggestive about the pathomechanisms of GBM distortion in Alport’s syndrome. As is the case for other genetic collagen diseases, a large body of data suggests that an abnormal collagen chain does not incorporate intracellularly into a functional triple-helical molecule; instead, it is degraded intracellularly.[127] It is also evident that α3:α4:α5 trimers can be formed only if all chains are present intracellularly. Thus, if one chain is abnormal or absent and a trimer cannot be formed, then the other two chains are degraded. In response to the absence of α3:α4:α5 form trimers, the embryonic α1:α1:α2 form replaces them. However, this isoform is not capable of forming a structurally functional adult GBM. Similar lack of developmental switch has been described in the cochlear basement membrane in patients with Alport’s syndrome who have hearing loss.[160]

In patients with X-linked Alport’s syndrome, the α3-, α4-, and α5-chains are usually completely undetectable in immunostained kidney sections. However, in autosomal recessive Alport’s syndrome, in which the defects are in the COL4A3 or COL4A4 genes, the α5-chain is expressed in Bowman’s capsule, where it is incorporated into an α5:α5:α6 trimer.[112]

Courtesy of: Taal: Brenner and Rector's The Kidney, 9th ed.

[tyven]

is this like stockholm syndrome except it happens when you are at the airport for too long and so you dont want to leave your gate, not even for a cinnabon?

[Guyverarmor]

Shit was going good to Tyven had to pull a Bane

Good look CS btw

[tyven]

every thread i touch improves.