Topoisomerase I and II consensus sequences in a 17-kB deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome

Yasuyoshi Ueki, Ichiro Naito, Toshitaka Oohashi, Manabu Sugimoto, Tsugio Seki, Hidekatsu Yoshioka, Yoshikazu Sado, Hiroshi Sato, Takashi Sawai, Fumiaki Sasaki, Mitsumasa Matsuoka, Seiji Fukuda, Yoshifumi Ninomiya

Research output: Contribution to journalArticle

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Abstract

Diffuse esophageal leiomyomatosis (DL), a benign smooth-muscle-cell tumor, is characterized by abnormal cell proliferation. DL is sometimes associated with X-linked Alport syndrome (AS), an inherited nephropathy caused by COL4A5 gene mutations. COL4A5 is tightly linked, in a head-to-head fashion, to the functionally related and coordinately regulated COL4A6 gene. No X-linked AS cases are due to COL4A6 mutations, but all DL/AS cases are always associated with deletions spanning the 5' regions of the COL4A5/COL4A6 cluster. Unlike the COL4A5 breakpoints, those of COL4A6 are clustered within intron 2 of the gene. We identified a DL/AS deletion and the first characterization of the breakpoint sequences. We show that a deletion eliminates the first coding exon of COL4A5 and the first two coding exons of COL4A6. The breakpoints share the same sequence, which, in turn, is closely homologous to the consensus sequences of topoisomerases I and II. Additional DNA evidence suggested that the male patient is a somatic mosaic for the mutation. Immunohistochemical analysis using α-chain-specific monoclonal antibodies supported this conclusion, since it revealed the absence of the α5(IV) and α6(IV) collagen chains in most but not all of the basement membranes of the smooth-muscle-cell tumor. We also documented a similar segmental staining pattern in the glomerular basement membranes of the patient's kidney. This study is particularly relevant to the understanding of DL pathogenesis and its etiology.

Original languageEnglish
Pages (from-to)253-261
Number of pages9
JournalAmerican Journal of Human Genetics
Volume62
Issue number2
DOIs
Publication statusPublished - Feb 1998

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Leiomyomatosis
Hereditary Nephritis
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Consensus Sequence
Smooth Muscle Tumor
Genes
Mutation
Smooth Muscle Myocytes
Exons
Glomerular Basement Membrane
Basement Membrane
Introns
Collagen
Monoclonal Antibodies
Cell Proliferation
Staining and Labeling
Kidney
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

Topoisomerase I and II consensus sequences in a 17-kB deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome. / Ueki, Yasuyoshi; Naito, Ichiro; Oohashi, Toshitaka; Sugimoto, Manabu; Seki, Tsugio; Yoshioka, Hidekatsu; Sado, Yoshikazu; Sato, Hiroshi; Sawai, Takashi; Sasaki, Fumiaki; Matsuoka, Mitsumasa; Fukuda, Seiji; Ninomiya, Yoshifumi.

In: American Journal of Human Genetics, Vol. 62, No. 2, 02.1998, p. 253-261.

Research output: Contribution to journalArticle

Ueki, Yasuyoshi ; Naito, Ichiro ; Oohashi, Toshitaka ; Sugimoto, Manabu ; Seki, Tsugio ; Yoshioka, Hidekatsu ; Sado, Yoshikazu ; Sato, Hiroshi ; Sawai, Takashi ; Sasaki, Fumiaki ; Matsuoka, Mitsumasa ; Fukuda, Seiji ; Ninomiya, Yoshifumi. / Topoisomerase I and II consensus sequences in a 17-kB deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome. In: American Journal of Human Genetics. 1998 ; Vol. 62, No. 2. pp. 253-261.
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abstract = "Diffuse esophageal leiomyomatosis (DL), a benign smooth-muscle-cell tumor, is characterized by abnormal cell proliferation. DL is sometimes associated with X-linked Alport syndrome (AS), an inherited nephropathy caused by COL4A5 gene mutations. COL4A5 is tightly linked, in a head-to-head fashion, to the functionally related and coordinately regulated COL4A6 gene. No X-linked AS cases are due to COL4A6 mutations, but all DL/AS cases are always associated with deletions spanning the 5' regions of the COL4A5/COL4A6 cluster. Unlike the COL4A5 breakpoints, those of COL4A6 are clustered within intron 2 of the gene. We identified a DL/AS deletion and the first characterization of the breakpoint sequences. We show that a deletion eliminates the first coding exon of COL4A5 and the first two coding exons of COL4A6. The breakpoints share the same sequence, which, in turn, is closely homologous to the consensus sequences of topoisomerases I and II. Additional DNA evidence suggested that the male patient is a somatic mosaic for the mutation. Immunohistochemical analysis using α-chain-specific monoclonal antibodies supported this conclusion, since it revealed the absence of the α5(IV) and α6(IV) collagen chains in most but not all of the basement membranes of the smooth-muscle-cell tumor. We also documented a similar segmental staining pattern in the glomerular basement membranes of the patient's kidney. This study is particularly relevant to the understanding of DL pathogenesis and its etiology.",
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AU - Oohashi, Toshitaka

AU - Sugimoto, Manabu

AU - Seki, Tsugio

AU - Yoshioka, Hidekatsu

AU - Sado, Yoshikazu

AU - Sato, Hiroshi

AU - Sawai, Takashi

AU - Sasaki, Fumiaki

AU - Matsuoka, Mitsumasa

AU - Fukuda, Seiji

AU - Ninomiya, Yoshifumi

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