Smooth muscle tumors associated with X-linked Alport syndrome: Carrier detection in females

Abstract

X-linked Alport syndrome (AS) associated with diffuse esophageal leiomyomatosis (DL) has been reported to be due to deletions removing the 5' ends of both the COL4A5 and COL4A6 genes, encoding the alpha 5 and alpha 6 chains of type IV collagen, respectively, whereas a variety of mutations in COL4A5 has been identified in patients with AS alone. Here we report three additional DL-AS patients who also display deletions removing the 5' ends of both COL4A5 and COL4A6 genes. Furthermore, we tracked the mutation in 15 females belonging to six DL-AS families by gene copy number determination. We found that, like AS, DL is transmitted as an X-linked dominant trait but, contrary to AS, DL is fully penetrant and completely expressed in females. These results are in agreement with our previous work suggesting that DL could be due to a dominant effect of an abnormal alpha 6 (IV) collagen chain. Finally, we have detected a similar deletion of the COL4A5 and COl4A6 genes in a DL affected female who showed no sign of nephropathy, demonstrating the AS carrier status of this DL patient. These results emphasize the importance of molecular analysis of female DL patients for genetic counseling.

X-Linked Alport Syndrome

“…Hearing loss, usually occurring after 30 to 40 yr of age, was observed in 28% of patients, and ocular changes, mostly macular flecks, were detected in 15%. Ten patients had diffuse esophageal leiomyomatosis; as previously shown, there is no correlation between the presence of leiomyomatosis and the severity of the renal disease (33).…”

Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis-Alport syndrome (DL-AS) locus define the DL critical region

“…We have also shown that DL acts as a dominant condition, that DL-AS patients consistently carry COL4A5-COL4A6 deletions with COL4A6 breakpoints located in the large intron 2 of the gene, and that AS patients with deletions extending further into COL4A6. at least those reported to date, display no tumors Dahan et al, 1995). These results suggest that cell proliferation is due to a gain-of-function mutation involving either COL4A6, via the production of a truncated a6(IV) chain, or another, as yet unidentified, gene lying in the COL4A6 intron 2 and disrupted by the deletions.…”

The clinical spectrum of type IV collagen mutations

“…Previously, it has been reported that in 15-18% of the cases no family history of Alport syndrome was present , but this number included both de novo mutations and single autosomal recessive cases (Yoshikawa et al, 1987;Atkin et al, 1988). The large rearrangements may be due to misalignment of repeat sequences in the large COL4A5 and COL4A6 introns (Dahan et al, 1995). A percentage of 10-15% new mutations is comparable with other X-linked disorders.…”

“…The deletion breakpoint is always located in intron 2 of the COL4A6 gene (Zhou et al, 1993a). Alport patients with more extended deletions farther downstream COL4A6 do not have leiomyomatosis (Heidet et al, 1995). Thus far, no mutations have been identified in the COL4A6 gene only in patients with Alport syndrome (Zhou et al, 1993a;Heiskari et al, 1996).…”