Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Collagen type IV, alpha 5

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

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%).

Gene Structure

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.

Expression

Collagen IV alpha 5 is a component of the basement membrane in many organs. However in the glomerular basement membrane, the cornea and cochlea its presence is of most importance as in these places no other alpha chains exist to replace its function. Concllusively, its absence causes specific kidney, eye and hearing symptoms.

Of special immunopathologic diagnostic importance is the presence of collagen IV alpha 5 in the skin and in the Bowman capsule. In the kidney it is easiliy accessible to biopsy, and the absence of the other important Alport collagen IV types 3 and 4 in the Bowman capsule is of importance in differentiating the type of Alport syndrome.

Phenotype

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.

Pathology

The different alpha chains of collagen IV form a heterotrimer of variable alpha 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.

Test Strategy

Early confirmation of diagnosis to provide preemptive therapy. Family counsuling.

Interpretation

Hemizygous male patients suffer from Alport syndrome while heterozygous females show milder symptoms varying from microscopic hematuria to Alport syndrome whose onset is significantly later tha in male patients of the same family.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Alport Syndrome
COL4A3
COL4A4
COL4A5
Goodpasture syndrome
COL4A3
COL4A3BP
COL4A5

References:

1.

Nagel M et al. (2005) Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome.

[^]
Update: Sept. 26, 2018