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      A New Point Mutation in the COL4A5 Gene Described in a Spanish Family with X-Linked Alport Syndrome


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          Background/Aim: Alport syndrome is a hereditary glomerulonephritis, X-linked in 85% of the cases. This form is associated with mutations in the COL4A5 gene which encodes the α5 chain of type IV collagen. We have performed the mutational analysis of the COL4A5 gene in a Spanish family with X-linked Alport syndrome. Methods: We have analyzed three polymorphic markers close to the gene to confirm the X chromosome linkage. By means of the PCR technique, we have screened the 51 exons of the gene. Results: The segregation of the alleles from the analyzed markers was in agreement with the X linkage. Direct sequencing of PCR-amplified products has shown a CCT-to-CTT change in exon 25, resulting in substitution of a proline for a leucine at position 619 of the polypeptide chain (nucleotide 2058). Conclusions: Although proline is considered a nonconserved amino acid, it is essential, upon hydroxylation, in the maintenance of a stable alpha chain triple-helix collagen. Furthermore, the change cosegregates with the disease in all affected members of the family, not being present in 80 control chromosomes. This represents a new mutation in the COL4A5 gene found in the Spanish population.

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          Most cited references2

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          Making the diagnosis of Alport's syndrome.

          Y Pirson (1999)
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            Glycosylation/Hydroxylation-induced stabilization of the collagen triple helix. 4-trans-hydroxyproline in the Xaa position can stabilize the triple helix.

            We have shown recently that glycosylation of threonine in the peptide Ac-(Gly-Pro-Thr)(10)-NH(2) with beta-d-galactose induces the formation of a collagen triple helix, whereas the nonglycosylated peptide does not. In this report, we present evidence that a collagen triple helix can also be formed in the Ac-(Gly-Pro-Thr)(10)-NH(2) peptide, if the proline (Pro) in the Xaa position is replaced with 4-trans-hydroxyproline (Hyp). Furthermore, replacement of Pro with Hyp in the sequence Ac-(Gly-Pro-Thr(beta-d-Gal))(10)-NH(2) increases the T(m) of the triple helix by 15.7 degrees C. It is generally believed that Hyp in the Xaa position destabilizes the triple helix because (Pro-Pro-Gly)(10) and (Pro-Hyp-Gly)(10) form stable triple helices but the peptide (Hyp-Pro-Gly)(10) does not. Our data suggest that the destabilizing effect of Hyp relative to Pro in the Xaa position is only true in the case of (Hyp-Pro-Gly)(10). Increasing concentrations of galactose in the solvent stabilize the triple helix of Ac-(Gly-Hyp-Thr)(10)-NH(2) but to a much lesser extent than that achieved by covalently linked galactose. The data explain some of the forces governing the stability of the annelid/vestimentiferan cuticle collagens.

              Author and article information

              S. Karger AG
              April 2002
              08 April 2002
              : 90
              : 4
              : 455-459
              aCentre d’Investigacions en Bioquímica i Biologia Molecular i bDepartament de Nefrologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain
              54734 Nephron 2002;90:455–459
              © 2002 S. Karger AG, Basel

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              Page count
              Figures: 2, References: 40, Pages: 5
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/54734
              Self URI (text/html): https://www.karger.com/Article/FullText/54734
              Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
              Original Paper

              Cardiovascular Medicine,Nephrology
              Alport syndrome,COL4A5 mutation,Collagenous domain,Exon 25,Linkage analysis


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