儿童的遗传性肾病讲座.pptVIP

Similarly to all basement membranes, the main components of the GBM include type IV collagen, laminin, (heparan sulfate) proteoglycans such as agrin and nidogen. Note: heparan sulfate proteoglycans may be responsible for the negative charge as well. * Coming to the collagen defects, the type IV collagen family comprises six distinct chains [a1 (IV)–a 6 (IV)] encoded by six genes (COL4A1–COL4A6) that are arrayed in pairs on three chromosomes: Type IV collagen chains form three forms of heterotrimeric units in mammalian basement membranes: a1a1a2, a3a4a5 and a5a5a6. Deficiency in one of these forms result in excess accumulation of the other forms. Interactions between like heterotrimers result in open, nonfibrillar networks in basement membranes. The a3a4a5 type IV collagen network predominates in mature mammalian GBM. * Therefore disorders of the GBM can be classified according to which protein is affected: Mutations in type IV collagen have been associated with several renal disorders – Alport syndrome, thin basement membrane nephropathy (TBMN) and HANAC (Hereditary Angiopathy with Nephropathy, Aneurysms, and muscle Cramps) syndrome – While mutations in laminin have been associated with Pierson syndrome. However, Pierson syndrome does not present with hematuria, but rather congenital NS. In addition, dysregulation of GBM protein synthesis due to mutations in the transcription factor LMX1B is associated with nail-patella syndrome, but again, this usually presents with a problem of proteinuria/nephrotic syndrome. * There are three genetic types of Alport syndrome: XLAS, ARAS and ADAS. XLAS accounts for about 80% of patients and results from mutations in COL4A5 , which encodes the a5 -chain of type IV collagen [a5 (IV)]. ARAS (about 15% of patients) arises from mutations affecting affecting both alleles of COL4A3 , which encodes a3 (IV), or COL4A4 , which encodes a4 (IV). About 5% have ADAS due to heterozygous mutations in COL4A3 or COL4A4. In males w