Scientific background:

Summary: This is one of two genes responsible for autosomal Alport syndrome. Depending on the type of mutation dominant or recessive inheritance is possible. The number of mutated alleles defines the severity of symptoms. Only one allele affected leads to benign hematuria, two alleles Alport syndrome.

Gene: The gene COL4A3 is located on chromosome 2 (2q36-q37) in a head-to-head position with the gene COL4A4 . Both genes probably use the same promotor. The size is about 150kb. There exists 3 splice variants with 51, 49 and 48 exons.

Pathology: The basement membranes of the body mainly consists of collagen type IV. Herein the alpha chains 3, 4 and 5 plays an special role. The highly specialized basement membranes in glomerulum, inner ear and at some ocular locations consists of these chains. Therefore, if one of these chains is disturbed symptoms in these organs are possible.

Clinical signs: This gene is responsible for autosomal recessive Alport syndrome. That means: in homozygous state a full blown clinical picture of Alport syndrome can be seen that is characterized by progressive nephritis, sensorineural deafness and a plethora of ocular abnormalities. In heterozygous state the clinical picture seems to be equivalent to benign familial hematuria.

Epidemiology: The Alport syndrome is responsible for about 0,5-1% of patients on dialysis in Western countries. The autosomal recessive form makes only 15-20% of these.

Interpretation: The detection of a mutation confirms autosomal recessive Alport syndrome.

Test strategy: This investigation is required when the diagnosis of autosomal recessive Alport syndrome has to be confirmed.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		20 working days
		Effort		large
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		6 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.
	research test	Method		Gene dosage measurements
		Turn-around time		20 working days
		Effort		large
		Specimen		DNA
		Quality assessment		Internal quality control only
	Of the gene rearrangements, this method is useful to detect large deletions or duplications.

Literature: 

Umfassende medizinische Information zum Alport-Syndrom
Die sehr aktive deutsche Selbsthilfegruppe
Nagel M et al. (2005) Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome.