title: Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis.
abstract: Alport syndrome-diffuse leiomyomatosis (AS-DL, OMIM: 308940) is a rare variant of the X-linked Alport syndrome that shows overgrowth of visceral smooth muscles in the gastrointestinal, respiratory and female reproductive tracts in addition to renal symptoms. AS-DL results from deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes, but deletion breakpoints between COL4A5 and COL4A6 have been determined in only four cases. Here, we characterize deletion breakpoints in five AS-DL patients and show a contiguous COL4A6/COL4A5 deletion in each case. We also demonstrate that eight out of nine deletion alleles involved sequences homologous between COL4A5 and COL4A6. Most breakpoints took place in recognizable transposed elements, including long and short interspersed repeats, DNA transposons and long-terminal repeat retrotransposons. Because deletions involved the bidirectional promoter region in each case, we suggest that the occurrence of leiomyomatosis in AS-DL requires inactivation of both genes. Altogether, our study highlights the importance of homologous recombination involving multiple transposed elements for the development of this continuous gene syndrome and other atypical loss-of-function phenotypes.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Minamikawa
authors.affiliation: Department of Pediatrics, Tokai University Oiso Hospital, Kanagawa, Japan.|Division of Human Genetics, National Institute of Genetics, Mishima, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Oka
authors.affiliation: Department of Nephrology, Kyoto University, Kyoto, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Morisada
authors.affiliation: Division of Nephrology, Saitama Children's Medical Center, Saitama City, Saitama, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Fujinaga
authors.affiliation: Department of Pediatric Nephrology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: China
authors.initials: C
authors.lastname: Nagano
authors.affiliation: Department of Pediatric Nephrology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Gotoh
authors.affiliation: Department of Nephrology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Eihiko
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Department of Pediatrics, University of Occupational and Environmental Health, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Morishita
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamamura
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ninchoji
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaito
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Morioka
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: University of Southampton Faculty of Medicine, Southampton, UK.
authors.forename: Igor
authors.initials: I
authors.lastname: Vorechovsky
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
mesh_terms: D001483:Base Sequence; D024141:Collagen Type IV / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D018231:Leiomyomatosis / Q000150:complications* / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000150:complications* / Q000235:genetics*
chemical_list: C478159:COL4A5 protein, human; C559044:COL4A6 protein, human; D024141:Collagen Type IV