Alport syndrome: clinical, molecular and genetic aspects

Alport Syndrome (AS) is a genetic disorder of basement membrane involving type IV collagen molecules. It has been recognized for many years that males and females with AS may show a different clinical course; the progression of the disease is more severe in males. Males present hematuria in early childhood, development of progressive sensorineural deafness during school years, and end-stage renal disease and ocular abnormalities in the late teens or early twenties. Females show a variable clinical course, and few are as severely affected as males. In formal genetic terms, this suggests that AS has a partially dominant X-linked inheritance, i.e. the mutation occurs in a gene located on the X-chromosome, while the normal allele on the other X in females partially corrects the defect. In some pedigrees, the disease is transmitted from male to male suggesting the existence of an autosomal dominant form the molecular basis of which remains unknown. In the rare autosomal recessive form females are as severely affected as males, whereas parents are healthy. Abnormalities of type IV collagen have been implicated as in the pathogenesis of AS. There are at least six type IV collagen chains present in basement membranes. The primary defect of the common X-linked AS affects the COL4A5 gene which has been mapped to Xq22, while alterations in COL4A3 or COL4A4, which map on chromosome 2, are responsible for the autosomal recessive form. This review will examine all the clinical features that characterize the Alport syndrome, recent findings on the molecular biology of type IV collagen chains, and the mutation of α5 (IV) chains which have been found so far.