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      A Novel Mutation of COL4A3 Presents a Different Contribution to Alport Syndrome and Thin Basement Membrane Nephropathy

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          Abstract

          Background: Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are heterogeneous renal hereditary diseases. Mutations of COL4A3 and COL4A4 genes were reported to be the underlying pathogenicity in both diseases. However, the mechanism of the same mutation causing totally different clinical processes and outcomes in AS and TBMN is still not clear. Subjects and Methods: Mutations of all coding exons of COL4A3 and COL4A4 were screened in a patient with autosomal recessive Alport syndrome (ARAS) of a Chinese Han consanguineous family by means of PCR and direct sequencing. Furthermore, the identified mutation was validated by restriction endonuclease AvaII in all 20 members in his family, as well as 46 patients with TBMN, 2 patients with AS from another two families, and 50 healthy controls. Results: A novel missense mutation (3725G>A, G1242D) in exon 42 of COL4A3 was identified in the proband in the homozygous form. This pathogenic mutation was demonstrated in all carriers who presented with hematuria or mild proteinuria in the heterozygous form, whereas it was not detected in others whose urinalysis was normal within the family. In addition, 10 polymorphisms, including 1 non-glycine missense variant and 9 neutral polymorphisms, were detected in COL4A3/COL4A4. Conclusion: The novel mutation (3725G>A, G1242D) of COL4A3 was the underlying pathogenic role in the homozygous form in ARAS and in the heterozygous form in TBMN within an identical family. The result provided a potentially useful clue for the functional investigation of COL4A3 in these two hereditary glomerular disorders.

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          Most cited references 12

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          Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.

          Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.
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            COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.

            COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome. Mutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported, and other genes and non-genetic factors may be involved. We analyzed 36 ATS patients for COL4A3 and COL4A4 mutations by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Sporadic patients who had tested negative for COL4A5 mutations were included with typical cases of autosomal recessive ATS to secure a better definition of the phenotype spectrum. We identified seven previously undescribed COL4A3 mutations: in two genetic compounds and three heterozygotes, and one in COL4A4. In agreement with the literature, some of the mutations of compound heterozygotes were associated with microhematuria in healthy heterozygous relatives. The mutations of heterozygous patients are likely dominant, since no change was identified in the second allele even by sequencing, and they are predicted to result in shortened or abnormal chains with a possible dominant-negative effect. In addition, both genes showed rare variants of unclear pathogenicity, and common polymorphisms that are shared in part with other populations. This study extends the mutation spectrum of COL4A3 and COL4A4 genes, and suggests a possible relationship between production of abnormal COL IV chains and dominant expression of a continuous spectrum of phenotypes, from ATS to BFH.
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              Making the diagnosis of Alport's syndrome.

               Y Pirson (1999)
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2007
                September 2007
                24 August 2007
                : 27
                : 5
                : 538-544
                Affiliations
                Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
                Article
                107666 Am J Nephrol 2007;27:538–544
                10.1159/000107666
                17726307
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, Tables: 2, References: 20, Pages: 7
                Categories
                Original Report: Laboratory Investigation

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