Editor—Alport syndrome (AS) is a hereditary nephritis characterised by haematuria, proteinuria, and chronic renal failure associated with progressive high tone sensorineural deafness and characteristic eye lesions (macular flecks and anterior lenticonus1). At the molecular level, X linked AS, which is the most common form, is caused by mutations in COL4A5 , a type IV collagen gene expressed in the glomerular basement membrane of the kidney.2 Mutations in COL4A5 cause progressive kidney damage usually leading to renal failure in affected males in early adulthood (20-25 years, juvenile form). A small proportion of COL4A5 mutations cause a later onset form of AS with ESRF in males at >31 years, although nephritis is apparent much earlier than this. Heterozygous females are generally mildly affected and often do not develop renal failure. We report here the identification of three apparently mosaic parents (two mothers and one father) of affected subjects. In the case of the mosaic father, an unusually mild AS phenotype was observed which may be a consequence of his mosaicism. The COL4A5 gene is composed of 51 exons spread over 250 kb of genomic DNA, which generate a 6.5 kb transcript encoding a 1685 amino acid protein3 and has been the subject of several large mutation studies.4-6 We have …

Leiomyomata of the esophagus are sporadic benign tumors of unknown etiology. We studied a collection of nine tumors for the expression of extracellular matrix components and found the same aberrant expression pattern as previously observed in inherited diffuse leiomyomatosis. We demonstrate here the occurrence of a somatic deletion at the COL4A5/COL4A6 locus at Xq22 in a frozen leiomyoma sample. These data confirm the hypothesis that the same underlying etiology is responsible for circumscribed smooth muscle proliferation in sporadic leiomyomata as for diffuse smooth muscle cell proliferation in inherited diffuse leiomyomatosis.

Diffuse leiomyomatosis (DL) with Alport syndrome (AS) has been shown to be associated with contiguous gene deletions of the COL4A5 and COL4A6 genes, with the COL4A6 breakpoint of the deletions invariably located in the large intron 2 of the gene. We describe four YAC clones covering the locus and a refined restriction map of the entire COL4A6 gene. These resources have allowed us to make a precise estimate of the size of COL4A6 introns 2 and 3, as well as the size of the gene itself. We also describe five novel deletions which, in conjunction with previous reports, allow the definition of a 90-kb critical region in which to search for a gene or other entity involved in the pathogenesis of DL.

Inherited diffuse esophageal leiomyomatosis a benign tumor involving smooth muscle cells of the whole esophagus, is frequently associated with X-linked Alport syndrome, a hereditary disease of type IV collagen. Families with this condition are consistently found to have deletions encompassing the 5' ends of both the alpha 5 chain of type IV collagen (COL4A5) and the alpha 6 chain of type IV collagen (COL4A6) genes, always limited in COL4A6 to exons 1', 1, and 2. On the contrary, patients with COL4A5/COL4A6 deletions extending further into COL4A6 display no such tumors. Despite the deletion, a COL4A6 transcript including exon 4, but not exon 3, was found in a tumor sample, raising the possibility of the involvement of a truncated alpha 6(IV) chain in the tumorous process. Using immunohistochemistry and in situ hybridization methods, we analyzed the expression and distribution of the alpha 6 chain of type IV collagen in tumors in comparison with that of normal, fetal, and mature esophagus. We also studied associated changes in tumor basement membrane composition and in tumor-cell integrin subunit distribution. No labeling with alpha 6(IV) antibodies was detected in tumors, ruling out the hypothesis of a stably integrated truncated alpha 6(IV) chain in tumor basement membranes. In contrast, despite the deletions of the first two exons of the gene and its 5' end, a COL4A6 transcript is clearly expressed by tumor cells. This finding raises the question of a potential role for this RNA in the tumor process. The absence of the alpha 6(IV) chain is associated with the absence of the alpha 5(IV) chain, as was suggested by the COL4A5 deletion. An additional striking feature is the absence of the beta 1 chain of laminin in tumor basement membranes and the lack of or uneven expression of the alpha 5 integrin subunit. These findings show that dramatic changes in the composition of the matrix and the expression of integrin receptors also occur in this benign tumorous process.

A population of 35 Alport syndrome patients, defined by strict diagnostic criteria, was screened for mutations in 23 exons of the COL4A5 gene by SSCP analysis. Mobility shifts were observed in 12 out of 35 patients and were shown to represent genuine mutations. 9 of these were glycine substitutions in the collagenous domain (in exons 20, 25, 26, 29, 31, and 41), 2 were small deletions resulting in frameshifts (in exons 21 and 31), and one was a splice site mutation (in exon 12). (C) 1995 Wiley-Liss, Inc.

Linkage analysis was carried out in two British families with incontinentia pigmenti (IP). Both showed exclusion at several markers in Xp and proximal Xq and showed probable linkage to the DXS52 and F8C loci in Xq28. This suggests that in these families the disease locus is IP2. Using a method based on the androgen receptor gene, and confirming the results where possible at the PGK-1 and DXS255 loci, it was shown that in affected females the maternally inherited X chromosome, where it could be identified, is inactive in the majority of cells.

Journal Article An 8 bp deletion in exon 51 of the COL4A5 gene of an Alport syndrome patient Get access E. Boye, E. Boye * * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar F.A. Flinter, F.A. Flinter Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Bobrow, M. Bobrow Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Harris A. Harris 1Paediatric Molecular Genetics, Department of Paediatrics, Institute of Molecular Medicine, John Radcliffe HospitalOxford 0X3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 2, Issue 5, May 1993, Pages 595–596, https://doi.org/10.1093/hmg/2.5.595 Published: 01 May 1993 Article history Received: 07 January 1993 Revision received: 23 February 1993 Accepted: 23 February 1993 Published: 01 May 1993

Alport syndrome (AS), an X-linked kidney disorder, has been shown to be caused by mutations in the gene for the alpha 5-chain of type IV collagen (COL4A5), which maps to Xq22. On the basis of the results of conventional Southern blot analysis of AS patient DNAs, we employed pulsed-field gel electrophoresis to characterize further three gene rearrangements at the 3'-end of alpha 5(IV). We were able to construct long-range restriction maps for all three of these patients and deduce the extent and nature of each rearrangement. One of these mutations is a 450-kb simple deletion that includes 12 kb of the alpha 5(IV) gene. A second mutation has been shown to be a direct duplication of 35 kb of alpha 5(IV) genomic DNA, and a third mutation involves a complex insertion/deletion event resulting in an overall loss of 25 kb.