Scientific background:

Summary: This gene is the most important Alport gene. Mutations account for x-linked Alport syndrome.

Gene: The Gen COL4A5 coding alpha chain 5 of collagen type IV is about 260kb in size. The gene is localized on x chromosome in head to head orientation with the COL4A6 gene. There are 3 splicing variants known. the constist of 51 or 52 exons. The physiological importance of these variants is not known yet.

Pathology: The different alpha chains of collagen IV form a heteritrimer of variable apha chain composition. This heterotrimer has the form of a triple helix. Important for the formation of the helical structure is the occurrence of the amino acid glycin at every third position (G-X-Y). The chains are connected by disulfide bounds. This fact is important for the resistance of collagen to collagenases. This alpha chain is a constituent of basement membranes in glomerulum, cochlea and eye.

Clinical signs: Clinical findings are hereditary nephritis, sensoneural deafness an a plethora of ocular abnormalities. The nephritis starts with erythrocyturia and develops end stage renal disease. The lenticonus anterior is the most pathognomonic ocular abnormality. If in a family females are affected too a autosomal recessive form should be considered. After transplantation the patients might develop Goodpasture like clinical because there might not developed an immuno tollerance.

Epidemiology: The prevalence of COL4A5 mutations is 1:5,000 to 1:10,000. About 0.5% of adult patients on hemodialysis have Alport's syndrome. X-chromosomal Alport's syndrome is the most frequent form (85%).

Interpretation: Mutation screening is important for early and exact diagnosis. It is the only reliable method to enable preemptive therapy. It has to take into account that only about 50% of mutations can be found.

Test strategy: Early confirmation of diagnosis to provide preemptive therapy. Family counsuling.

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		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		19 working days
		Effort		large
		Specimen		DNA
		Quality assessment		Internal quality control only
	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.

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.