Persistent familial hematuria in children and the locus for thin basement membrane nephropathy

Abstract

This study examined how often children with persistent familial hematuria were from families where hematuria segregated with the known genetic locus for the condition known as benign familial hematuria or thin basement membrane nephropathy (TBMN) at COL4A3/COL4A4. Twenty-one unrelated children with persistent familial hematuria as well as their families were studied for segregation of hematuria with haplotypes at the COL4A3/COL4A4 locus for benign familial hematuria and at the COL4A5 locus for X-linked Alport syndrome. Eight families (38%) had hematuria that segregated with COL4A3/COL4A4, and four (19%) had hematuria that segregated with COL4A5. At most, eight of the other nine families could be explained by disease at the COL4A3/COL4A4 locus if de novo mutations, non-penetrant hematuria or coincidental hematuria in unaffected family members was present individually or in combination. This study confirms that persistent familial hematuria is not always linked to COL4A3/COL4A4 (or COL4A5) and suggests the possibility of a further genetic locus for benign familial hematuria. This study also highlights the risk of excluding X-linked Alport syndrome on the basis of the absence of a family history or of kidney failure.

Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases

“…The families of all 13 families had been studied previously for linkage and four (31%) had hematuria linked to the COL4A3/COL4A4 locus [9,19]. X-linked Alport syndrome was excluded in all families by linkage.…”

Difficulties in differentiating thin basement membrane disease from Alport syndrome

“…The first were Habib et al [9]. They werefollowedbyotherresearchers:Aaronset al [10], Langet al [11],Lamprechtet al [12],Lemminket al [13],Pigneraset al [14],andothers [15,16,17,18,19,20,21,22,23,24].Itwasestablishedthatboth diseases are accompanied by mutations in the CO-L4A3/COL4A4genes.However,basedontheavailable results of the research on the mutations in the COL4A3/COL4A4genes,nocleardiagnosticcriteria could be defined in order to distinguish thin basementmembranedisease,autosomaldominantAlport syndromeandautosomalrecessiveAlportsyndrome. Ofdiagnosticimportanceisthelackofreactionwith anti chains α3, α4 and α5 collagen type IV in the basementmembranesofrenalglomeruliandtubules (and the lack of reaction from the anti-α5 chain in theskin).…”

Discordance between skin biopsy and kidney biopsy in an X-linked carrier of Alport syndrome

“…However, early in the course of AS, thinning of the GBM may be the first abnormality seen on electron microscopy. Immunohistochemical studies of the GBM and EBM in male patients show lack of the α5(IV) chain in 80% of males [4], while heterozygous females often show segmental loss, probably explained by the Lyon hypothesis [1][2][3].…”

“…AS is a genetically heterogeneous disease with X-linked (affecting males more severely), autosomal recessive and autosomal dominant variants [1]. It is characterized by hematuria, proteinuria and progressive renal failure typically in males and often is associated with bilateral sensorineural hearing loss and, less commonly, ocular defects [1][2][3][4]. The X-linked form of AS is caused by mutations in the COL4A5 gene that encodes one of the six type IV collagen alpha chains.…”