Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene

Jens Michael Hertz, Ulf Persson, Inger juncker, Mårten Segelmark

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The X-linked form of Alport syndrome (AS) is caused by mutation in the COL4A5 gene located at Xq22.3 and encoding the alpha5-chain of type IV-collagen. More than 400 different mutations have so far been detected in the COL4A5 gene. Not all mutations, however, will be detected using an exon-by-exon mutation detection strategy such as SSCP analysis or direct sequencing. We have previously reported the results of SSCP analysis of 81 patients suspected of X-linked AS. Genomic DNA from these 81 patients was also analyzed for larger genomic rearrangements, using Southern blotting analysis. Abnormal band patterns were found in three patients, two of which were caused by single base substitutions in the coding region, also detected by the SSCP analysis. Here we report the results of the analysis of a larger structural COL4A5 rearrangement that escaped the SSCP analysis. The rearrangement was found to be an inversion of a 21 Mb fragment of the COL4A5 gene comprising exon 9 through 51 with proximal breakpoint within intron 8 at Xq22.3 and a distal breakpoint 56 kb upstream to the initiation codon in the RAB33A gene at Xq25. The inversion of exon 9 through 51 is expected to result in a truncated or absent alpha5(IV)-chain and has not previously been associated with AS. These findings emphasize the need for a supplement to mutation detection strategies such as SSCP analysis and direct sequencing, in order to detect more complicated structural COL4A5 rearrangements. Larger structural rearrangements constitute 2.3% (1/43) of the mutations in the present material.
OriginalsprogEngelsk
TidsskriftHuman Genetics
Vol/bind118
Udgave nummer1
Sider (fra-til)23-8
Antal sider6
ISSN0340-6717
DOI
StatusUdgivet - 2005

Fingeraftryk

Hereditary Nephritis
Single-Stranded Conformational Polymorphism
Mutation
Collagen Type IV
Initiator Codon
Southern Blotting
Introns
DNA

Citer dette

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title = "Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene",
abstract = "The X-linked form of Alport syndrome (AS) is caused by mutation in the COL4A5 gene located at Xq22.3 and encoding the alpha5-chain of type IV-collagen. More than 400 different mutations have so far been detected in the COL4A5 gene. Not all mutations, however, will be detected using an exon-by-exon mutation detection strategy such as SSCP analysis or direct sequencing. We have previously reported the results of SSCP analysis of 81 patients suspected of X-linked AS. Genomic DNA from these 81 patients was also analyzed for larger genomic rearrangements, using Southern blotting analysis. Abnormal band patterns were found in three patients, two of which were caused by single base substitutions in the coding region, also detected by the SSCP analysis. Here we report the results of the analysis of a larger structural COL4A5 rearrangement that escaped the SSCP analysis. The rearrangement was found to be an inversion of a 21 Mb fragment of the COL4A5 gene comprising exon 9 through 51 with proximal breakpoint within intron 8 at Xq22.3 and a distal breakpoint 56 kb upstream to the initiation codon in the RAB33A gene at Xq25. The inversion of exon 9 through 51 is expected to result in a truncated or absent alpha5(IV)-chain and has not previously been associated with AS. These findings emphasize the need for a supplement to mutation detection strategies such as SSCP analysis and direct sequencing, in order to detect more complicated structural COL4A5 rearrangements. Larger structural rearrangements constitute 2.3{\%} (1/43) of the mutations in the present material.",
keywords = "Chromosome Inversion, Chromosomes, Human, X, Collagen Type IV, Exons, Humans, Nephritis, Hereditary, Polymerase Chain Reaction",
author = "Hertz, {Jens Michael} and Ulf Persson and Inger juncker and M{\aa}rten Segelmark",
year = "2005",
doi = "10.1007/s00439-005-0013-0",
language = "English",
volume = "118",
pages = "23--8",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Heinemann",
number = "1",

}

Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene. / Hertz, Jens Michael; Persson, Ulf; juncker, Inger; Segelmark, Mårten.

I: Human Genetics, Bind 118, Nr. 1, 2005, s. 23-8.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene

AU - Hertz, Jens Michael

AU - Persson, Ulf

AU - juncker, Inger

AU - Segelmark, Mårten

PY - 2005

Y1 - 2005

N2 - The X-linked form of Alport syndrome (AS) is caused by mutation in the COL4A5 gene located at Xq22.3 and encoding the alpha5-chain of type IV-collagen. More than 400 different mutations have so far been detected in the COL4A5 gene. Not all mutations, however, will be detected using an exon-by-exon mutation detection strategy such as SSCP analysis or direct sequencing. We have previously reported the results of SSCP analysis of 81 patients suspected of X-linked AS. Genomic DNA from these 81 patients was also analyzed for larger genomic rearrangements, using Southern blotting analysis. Abnormal band patterns were found in three patients, two of which were caused by single base substitutions in the coding region, also detected by the SSCP analysis. Here we report the results of the analysis of a larger structural COL4A5 rearrangement that escaped the SSCP analysis. The rearrangement was found to be an inversion of a 21 Mb fragment of the COL4A5 gene comprising exon 9 through 51 with proximal breakpoint within intron 8 at Xq22.3 and a distal breakpoint 56 kb upstream to the initiation codon in the RAB33A gene at Xq25. The inversion of exon 9 through 51 is expected to result in a truncated or absent alpha5(IV)-chain and has not previously been associated with AS. These findings emphasize the need for a supplement to mutation detection strategies such as SSCP analysis and direct sequencing, in order to detect more complicated structural COL4A5 rearrangements. Larger structural rearrangements constitute 2.3% (1/43) of the mutations in the present material.

AB - The X-linked form of Alport syndrome (AS) is caused by mutation in the COL4A5 gene located at Xq22.3 and encoding the alpha5-chain of type IV-collagen. More than 400 different mutations have so far been detected in the COL4A5 gene. Not all mutations, however, will be detected using an exon-by-exon mutation detection strategy such as SSCP analysis or direct sequencing. We have previously reported the results of SSCP analysis of 81 patients suspected of X-linked AS. Genomic DNA from these 81 patients was also analyzed for larger genomic rearrangements, using Southern blotting analysis. Abnormal band patterns were found in three patients, two of which were caused by single base substitutions in the coding region, also detected by the SSCP analysis. Here we report the results of the analysis of a larger structural COL4A5 rearrangement that escaped the SSCP analysis. The rearrangement was found to be an inversion of a 21 Mb fragment of the COL4A5 gene comprising exon 9 through 51 with proximal breakpoint within intron 8 at Xq22.3 and a distal breakpoint 56 kb upstream to the initiation codon in the RAB33A gene at Xq25. The inversion of exon 9 through 51 is expected to result in a truncated or absent alpha5(IV)-chain and has not previously been associated with AS. These findings emphasize the need for a supplement to mutation detection strategies such as SSCP analysis and direct sequencing, in order to detect more complicated structural COL4A5 rearrangements. Larger structural rearrangements constitute 2.3% (1/43) of the mutations in the present material.

KW - Chromosome Inversion

KW - Chromosomes, Human, X

KW - Collagen Type IV

KW - Exons

KW - Humans

KW - Nephritis, Hereditary

KW - Polymerase Chain Reaction

U2 - 10.1007/s00439-005-0013-0

DO - 10.1007/s00439-005-0013-0

M3 - Journal article

VL - 118

SP - 23

EP - 28

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 1

ER -