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Jing Zhou - One of the best experts on this subject based on the ideXlab platform.
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Deletion spanning the 5′ ends of both the COL4A5 and COL4A6 genes in a patient with Alport's syndrome and leiomyomatosis
Human Mutation, 2005Co-Authors: Alessandra Renieri, Mario De Marchi, Lucia Galli, M T Bassi, Marisa Giani, Jing Zhou, Andrea BallabioAbstract:Alport's syndrome is characterized clinically by a nonimmune glomerulopathy, often accompanied by sensorineural hearing loss and lens abnormalities, frequently due to mutations in the COL4A5 gene. The association of AS with diffuse leiomyomatosis, a benign proliferation of smooth muscle that occurs most often in the esophagus, trachea, and female genitalia, has been reported. Recently, a deletion involving both the COL4A5 and COL4A6 genes has been reported in four unrelated families. We report an additional case with Alport's syndrome associated with leiomyomatosis carrying a deletion of both COL4A5 and COL4A6 genes. A detailed characterization of the genomic region involved in the deletion event has been performed. Our results demonstrate that the deletion removed exon l of COL4A5 and exons l and 2 of COL4A6. © 1994 Wiley-Liss, Inc.
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Tissue- and developmental stage-specific activation of α5 and α6(IV) collagen expression in the upper gastrointestinal tract of transgenic mice
Biochemical and biophysical research communications, 2003Co-Authors: Christine Herzog, Yoav Segal, Liyan Zhuang, Lucian Gorgan, Jing ZhouAbstract:Little is known about mechanisms regulating gene expression for the a chains of basement membrane type IV collagen, arranged head-to-head in transcription units COL4A1–COL4A2, COL4A3–COL4A4, and COL4A5–COL4A6, and implicated broadly in genetic diseases. To investigate these mechanisms, we generated transgenic mouse lines bearing 5 0 -flanking sequences of COL4A5 and COL4A6, cloned upstream of a lacZ reporter gene. A 3.8-kb fragment upstream of COL4A6 directs reporter gene expression in the esophagus, stomach, and duodenum, whereas a 13.8-kb fragment directs expression in the esophagus only. A 10.6-kb fragment upstream of COL4A5 directs expression in the esophagus. Coupled with evidence of long-range conservation between human and mouse non-coding sequences, described herein, our findings provide the first indication that highly specialized patterns characteristic of COL4A5–COL4A6 expression in vivo arise from effects of distributed cis-acting regulatory elements on a bidirectional proximal promoter, itself transcriptionally competent. 2003 Elsevier Inc. All rights reserved.
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Deletion mapping in Alport syndrome and Alport syndrome-diffuse leiomyomatosis reveals potential mechanisms of visceral smooth muscle overgrowth.
Human Mutation, 2003Co-Authors: Beth K. Thielen, Stefan M. Kren, Raoul D. Nelson, David F Barker, Jing Zhou, Yoav SegalAbstract:Diffuse leiomyomatosis is associated with the inherited kidney disease Alport syndrome, and characterized by visceral smooth muscle overgrowth within the respiratory, gastrointestinal and female reproductive tracts. Although partial deletions of the type IV collagen genes COL4A5 and COL4A6, paired head-to-head on chromosome Xq22, are known to cause diffuse leiomyomatosis, loss of function for type IV collagen does not explain smooth muscle overgrowth. To further clarify pathogenic mechanisms, we have characterized novel deletions in patients with Alport syndrome-diffuse leiomyomatosis or Alport syndrome alone. A 27.6-kb deletion, in a female with Alport syndrome-diffuse leiomyomatosis, is marked by the most proximal, i.e. most 5', COL4A5 breakpoint described to date. By comparing this deletion to others described here and previously, we have defined a minimal overlap region, only 4.2 kb in length and containing the COL4A5-COL4A6 proximal promoters, loss of which contributes to smooth muscle overgrowth. A novel deletion in a male with Alport syndrome alone is>1.4 Mb in length, encompassing COL4A5 and COL4A6 entirely, as well as neighboring genes. We postulate that loss of the 4.2-kb region in diffuse leiomyomatosis causes misregulation of neighboring genes, contributing to smooth muscle overgrowth. Deletion of the neighboring genes themselves may afford protection from this condition. © 2003 Wiley-Liss, Inc.
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Regulation of the paired type IV collagen genes COL4A5 and COL4A6. Role of the proximal promoter region.
The Journal of biological chemistry, 2000Co-Authors: Yoav Segal, Liyan Zhuang, Eric Rondeau, Jean Daniel Sraer, Jing ZhouAbstract:Abstract Tissue-specific expression patterns of the paired type IV collagen genes COL4A5 and COL4A6form the basis for organ involvement in X-linked Alport syndrome, a disorder in which these genes are mutated. We investigated the proximal promoter region of COL4A5 and COL4A6 using glomerular visceral epithelial cells, in which COL4A5 alone is transcribed; keratinocytes, in which the genes are co-transcribed; and additional model cell lines. By RNase protection assays, the intergenic region is 292 base pairs. Transcription start sites for two 5′ splice variants of COL4A6 are 1 kilobase apart. Transient transfections with reporter gene constructs revealed that the minimal promoters for COL4A5 and COL4A6 are within 100 base pairs of their respective transcription start sites and are functionally distinct. In further transfection, gel shift and footprinting assays, we defined a bidirectional positive regulatory element, which functions in several cell types, but not in glomerular visceral epithelial cells selectively transcribing COL4A5. The existence of separate promoters for COL4A5 andCOL4A6 permits fine control over their expression. Activation through the bidirectional element can bring about co-expression of the genes, exploiting their paired arrangement. Features of the proximal promoter region frame its roles in a hierarchy regulating type IV collagen gene expression.
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LINE-1 Elements at the Sites of Molecular Rearrangements in Alport Syndrome–Diffuse Leiomyomatosis
American journal of human genetics, 1999Co-Authors: Yoav Segal, Mario De Marchi, Andrea Ballabio, Alessandra Renieri, Bernard Peissel, York Pei, Jing ZhouAbstract:Deletions encompassing the 5' termini of the paired type IV collagen genes COL4A5 and COL4A6 on chromosome Xq22 give rise to Alport syndrome (AS) and associated diffuse leiomyomatosis (DL), a syndrome of disseminated smooth-muscle tumors involving the esophagus, large airways, and female reproductive tract. In this study, we report isolation and characterization of two deletion junctions. The first, in a patient described elsewhere, arose by a nonhomologous recombination event fusing a LINE-1 (L1) repetitive element in intron 1 of COL4A5 to intron 2 of COL4A6, resulting in a 13.4-kb deletion. The second, in a previously undescribed family, arose by unequal homologous recombination between the same L1 and a colinear L1 element in intron 2 of COL4A6, resulting in a>40-kb deletion. L1 elements have contributed to the emergence of this locus as a site of frequent recombinations by diverse mechanisms. These give rise to AS-DL by disruption of type IV collagen and perhaps other as yet unidentified genes, evidenced by deletions as small as 13.4 kb.
Yoshifumi Ninomiya - One of the best experts on this subject based on the ideXlab platform.
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clonal overgrowth of esophageal smooth muscle cells in diffuse leiomyomatosis alport syndrome caused by partial deletion in col4a5 and COL4A6 genes
Matrix Biology, 2011Co-Authors: Toshitaka Oohashi, Yasuyoshi Ueki, Rattiya Permpoon, Tomoki Yamatsuji, Yoshio Naomoto, Ichiro Naito, Noriaki Tanaka, Yoshifumi NinomiyaAbstract:This is a study of a patient who manifests all of the features of a diffuse leiomyomatosis-Alport syndrome (DL-ATS), and her two-year-old son who has already been diagnosed with Alport syndrome. Fourteen years ago, the patient underwent a partial esophageal resection followed by a replacement with jejunum. Recently, she underwent a surgical resection of the esophagus due to esophageal dysfunction. Genetic analyses of COL4A5 and COL4A6 on the X-chromosome were efficiently performed using the genomic DNA of her son. We have identified a novel deletion of 194-kb in length, encompassing COL4A5–COL4A6 promoters as well as nearly the entire large intron 1 of COL4A5 and intron 2 of COL4A6. To uncover the relationship of the esophagus-specific occurrence of the tumor and the expression of those genes, immunohistochemical analyses of type IV collagen α chains were conducted in the non-affected individuals. The esophageal smooth muscle-specific expression of α5(IV) and α6(IV) chains in the gastrointestinal tract was observed. Moreover, CAG repeat analysis of the androgen receptor gene and an immunohistochemical analysis in the leiomyoma revealed clonal overgrowth of the cells which received X-inactivation on the non-affected allele. These results may suggest that the dominant effect was caused by the partial deletion of the esophageal smooth muscle-specific genes, COL4A5 and COL4A6.
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Loss of expression of type IV collagen α5 and α6 chains in colorectal cancer associated with the hypermethylation of their promoter region
The American journal of pathology, 2006Co-Authors: Koei Ikeda, Yoshifumi Ninomiya, Yoshikazu Sado, Ken Ichi Iyama, Nobuyuki Ishikawa, Hiroshi Egami, Mitsuyoshi Nakao, Hideo BabaAbstract:Type IV collagen, a major component of the basement membrane (BM), is composed of six genetically distinct α(IV) chains, α1(IV) to α6(IV). Their genes are paired on three different chromosomes in a head-to-head arrangement. The α5(IV) gene (COL4A5) and the α6(IV) gene (COL4A6) are on chromosome Xq22 and are regulated by a bidirectional promoter. Loss of the α5(IV)/α6(IV) chains in epithelial BM occur in the early stage of cancer invasion. However, the regulatory mechanism of the specific loss of the α5(IV)/α6(IV) chains during cancer cell invasion is still undetermined. In the present study, we examined the expression of the α5(IV)/α6(IV) chains and the methylation profiles of the bidirectional promoter region of COL4A5/COL4A6 in colon cancer cell lines and colorectal tumor tissues. The expression of the α5(IV)/α6(IV) chains was down-regulated in colorectal cancer, and the loss of expression of the α5(IV)/α6(IV) chains was associated with the hypermethylation of their promoter region. In conclusion, the hypermethylation of the bidirectional promoter region of COL4A5/COL4A6 is one of the events that is responsible for the loss of expression of the α5(IV)/α6(IV) chains and the remodeling of the epithelial BM during cancer cell invasion.
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Absence of the α6(IV) Chain of Collagen Type IV in Alport Syndrome Is Related to a Failure at the Protein Assembly Level and Does Not Result in Diffuse Leiomyomatosis
The American journal of pathology, 1999Co-Authors: Keqin Zheng, Yoshifumi Ninomiya, Ichiro Naito, Yoshikazu Sado, Scott J. Harvey, Robert M. Jacobs, Paul S. ThornerAbstract:X-linked Alport syndrome is a progressive nephropathy associated with mutations in the COL4A5 gene. The kidney usually lacks the α3-α6 chains of collagen type IV, although each is coded by a separate gene. The molecular basis for this loss remains unclear. In canine X-linked hereditary nephritis, a model for X-linked Alport syndrome, a COL4A5 mutation results in reduced mRNA levels for the α3, α4, and α5 chains in the kidney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of α6 chain is under the same control, we studied smooth muscle cells from this animal model. We determined the canine COL4A5 and COL4A6 genes are separated by 435 bp, with two first exons for COL4A6 separated by 978 bp. These two regions are ≥ 78% identical to the human sequences that have promoter activity. Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the α6 mRNA level remained normal in affected male dog smooth muscle while the α5 mRNA level was markedly reduced. However, both α5 and α6 chains were absent at the protein level. Our results suggest that production of the α6 chain is under a control mechanism separate from that coordinating the α3-α5 chains and that the lack of the α6 chain in Alport syndrome is related to a failure at the protein assembly level, raising the possibility that the α5 and α6 chains are present in the same network. The lack of the α6 chain does not obviously result in disease, in particular leiomyomatosis, as is seen in Alport patients with deletions involving the COL4A5 and COL4A6 genes.
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Organization and expression of basement membrane collagen IV genes and their roles in human disorders.
Journal of Biochemistry, 1998Co-Authors: Yoshikazu Sado, Megumi Kagawa, Yasuyoshi Ueki, Tsugio Seki, Ryusuke Momota, Toshitaka Oohashi, Ichiro Naito, Yoshifumi NinomiyaAbstract:: Six distinct genes have been identified as belonging to the type IV collagen gene family. They can be organized into three sets, i.e., COL4A1/COL4A2, COL4A3/COL4A4, and COL4A5/COL4A6, which are localized on three different chromosomes in humans, 13, 2, and X, respectively. Within each set the genes are aligned head-to-head and their expression is regulated by bidirectional promoters between the genes. Transcriptional regulation of the COL4A1/COL4A2 set has been well characterized. The transcription of COL4A6 seems to be controlled by two alternative promoters. While collagen IV molecules composed of alpha1 and alpha2 chains are broadly distributed, molecules comprising combinations of the other four chains, alpha3-alpha6, are important components of specialized basement membranes. The precise chain composition of triple-helical molecules assembled from the alpha3-alpha6 chains is not entirely clear, but it is hypothesized that alpha3-alpha5 chains and alpha5 and alpha6 chains form heterotrimeric molecules. Several pieces of evidence indicate that alpha3/alpha4/alpha5 molecules and alpha5/alpha6 molecules are components of the basement membrane network. This helps explain the observation that the kidney and skin basement membranes from patients with Alport syndrome caused by mutations in the alpha5 coding gene, COL4A5, are defective in the alpha3, alpha4, and alpha6 chains together with the alpha5 chain. Large deletions involving the COL4A5 and COL4A6 genes have been found in rare cases of diffuse leiomyomatosis associated with Alport syndrome.
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Somatic deletion of the 5' ends of both the COL4A5 and COL4A6 genes in a sporadic leiomyoma of the esophagus.
The American journal of pathology, 1998Co-Authors: Laurence Heidet, Yoshifumi Ninomiya, Eileen Boye, Marie-claire Gubler, Xu Zhang, Yi Cai, Y. Sado, J.-f. Flejou, F. Fekete, Corinne AntignacAbstract:Leiomyomata of the esophagus are sporadic benign tumors of unknown etiology. We studied a collection of nine tumors for the expression of extracellular matrix components and found the same aberrant expression pattern as previously observed in inherited diffuse leiomyomatosis. We demonstrate here the occurrence of a somatic deletion at the COL4A5/COL4A6 locus at Xq22 in a frozen leiomyoma sample. These data confirm the hypothesis that the same underlying etiology is responsible for circumscribed smooth muscle proliferation in sporadic leiomyomata as for diffuse smooth muscle cell proliferation in inherited diffuse leiomyomatosis.
Laurence Heidet - One of the best experts on this subject based on the ideXlab platform.
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the renal lesions of alport syndrome
Journal of The American Society of Nephrology, 2009Co-Authors: Laurence Heidet, Marie-claire GublerAbstract:Alport syndrome is a hereditary, progressive, hematuric nephropathy characterized by glomerular basement membrane abnormalities with frequent hearing defects and ocular anomalies. The disease is associated with mutations in genes encoding the α3, α4, or α5 chains of type IV collagen, COL4A3 , or COL4A4 in the autosomal forms of the disease, COL4A5 in the more frequent X-linked variety. Ultrastructural changes in the glomerular basement membrane and frequent abnormal expression of type IV collagen chains in renal and skin basement membranes are crucial elements for the diagnosis of Alport syndrome, determination of the mode of inheritance, and genetic counseling. Animal models have provided invaluable tools to study the mechanisms leading to progressive deterioration of the glomerular basement membrane and ultimately to renal failure, and to evaluate benefits of potential targeted therapies.
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alport syndrome associated with diffuse leiomyomatosis col4a5 COL4A6 deletion associated with a mild form of alport nephropathy
Nephrology Dialysis Transplantation, 2002Co-Authors: Henning Mothes, Laurence Heidet, Corinne Antignac, Christelle Arrondel, Konrad Klaus Richter, Mariana Thiele, Ludwig Patzer, Yoshikazu Sado, Marie-claire Gubler, Jürgen ScheeleAbstract:BACKGROUND: The X-linked Alport syndrome (AS) is an inherited nephropathy due to mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen, a major component of the glomerular basement membrane (GBM). Here, we report a new kindred with the rare association of X-linked AS and diffuse leiomyomatosis (DL), which is a tumourous process involving smooth muscle cells of the oesophagus, the tracheobronchial tree and, in females, the genital tract. For this syndrome, an almost constant association of large COL4A5 rearrangements with a severe juvenile form of nephropathy has been described for male patients. METHODS: DNA rearrangement at the COL4A5-COL4A6 locus was studied in several members of this family using polymerase chain reaction and pulsed field gel electrophoresis. Furthermore, immunohistochemical staining of tumour and skin samples was performed. RESULTS: The affected patients in this family carry a 120 kb deletion by which the COL4A5 exon 1 and COL4A6 exons 1, 1', and 2 are removed. Immunohistochemical investigation of a skin biopsy of an affected male patient confirmed the absence of both the alpha5 and the alpha6 chains of type IV collagen in the basement membrane of the skin. Surprisingly, both affected male patients had a rather mild renal phenotype. CONCLUSIONS: This report shows that, contrary to what has been reported to date, patients suffering from AS associated with DL can be associated with a late onset renal failure (adult) form of nephropathy.
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Alport syndrome associated with diffuse leiomyomatosis: COL4A5‐COL4A6 deletion associated with a mild form of Alport nephropathy
Nephrology Dialysis Transplantation, 2002Co-Authors: Henning Mothes, Laurence Heidet, Corinne Antignac, Christelle Arrondel, Konrad Klaus Richter, Mariana Thiele, Ludwig Patzer, Yoshikazu Sado, Marie-claire Gubler, Jürgen ScheeleAbstract:BACKGROUND: The X-linked Alport syndrome (AS) is an inherited nephropathy due to mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen, a major component of the glomerular basement membrane (GBM). Here, we report a new kindred with the rare association of X-linked AS and diffuse leiomyomatosis (DL), which is a tumourous process involving smooth muscle cells of the oesophagus, the tracheobronchial tree and, in females, the genital tract. For this syndrome, an almost constant association of large COL4A5 rearrangements with a severe juvenile form of nephropathy has been described for male patients. METHODS: DNA rearrangement at the COL4A5-COL4A6 locus was studied in several members of this family using polymerase chain reaction and pulsed field gel electrophoresis. Furthermore, immunohistochemical staining of tumour and skin samples was performed. RESULTS: The affected patients in this family carry a 120 kb deletion by which the COL4A5 exon 1 and COL4A6 exons 1, 1', and 2 are removed. Immunohistochemical investigation of a skin biopsy of an affected male patient confirmed the absence of both the alpha5 and the alpha6 chains of type IV collagen in the basement membrane of the skin. Surprisingly, both affected male patients had a rather mild renal phenotype. CONCLUSIONS: This report shows that, contrary to what has been reported to date, patients suffering from AS associated with DL can be associated with a late onset renal failure (adult) form of nephropathy.
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structure of the human type iv collagen gene col4a3 and mutations in autosomal alport syndrome
Journal of The American Society of Nephrology, 2001Co-Authors: Laurence Heidet, Lionel Forestier, Bruno Gutierrez, Christophoros Stavrou, Geraldine Mollet, Christelle Arrondel, L Cohensolal, Marie-claire Gubler, Corinne AntignacAbstract:Abstract . Mutations in either the COL4A3 or the COL4A4 genes, encoding the α3 and α4 chains of type IV collagen, are responsible for the autosomal-recessive form of Alport syndrome, a progressive hematuric nephropathy characterized by glomerular basement membrane abnormalities. Reported here are the complete COL4A3 exon-intron structure and a comprehensive screen for mutations of the 52 COL4A3 exons in 41 unrelated patients diagnosed as having autosomal Alport syndrome. This resulted in the identification of 21 mutations that are expected to be causative. Furthermore, it is shown that heterozygous COL4A3 missense mutations, when symptomatic, can be associated with a broad range of phenotypes, from familial benign hematuria to the complete features of Alport syndrome nephropathy.
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Somatic deletion of the 5' ends of both the COL4A5 and COL4A6 genes in a sporadic leiomyoma of the esophagus.
The American journal of pathology, 1998Co-Authors: Laurence Heidet, Yoshifumi Ninomiya, Eileen Boye, Marie-claire Gubler, Xu Zhang, Yi Cai, Y. Sado, J.-f. Flejou, F. Fekete, Corinne AntignacAbstract:Leiomyomata of the esophagus are sporadic benign tumors of unknown etiology. We studied a collection of nine tumors for the expression of extracellular matrix components and found the same aberrant expression pattern as previously observed in inherited diffuse leiomyomatosis. We demonstrate here the occurrence of a somatic deletion at the COL4A5/COL4A6 locus at Xq22 in a frozen leiomyoma sample. These data confirm the hypothesis that the same underlying etiology is responsible for circumscribed smooth muscle proliferation in sporadic leiomyomata as for diffuse smooth muscle cell proliferation in inherited diffuse leiomyomatosis.
Judy Savige - One of the best experts on this subject based on the ideXlab platform.
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the importance of clinician patient and researcher collaborations in alport syndrome
Pediatric Nephrology, 2020Co-Authors: Michelle N Rheault, Michael J Randles, Andre Weinstock, Melissa Stepney, Neil A Turner, Judy Savige, Oliver Gross, Frances Flinter, Geppy Parziale, Jeffrey H MinerAbstract:Alport syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.
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expert consensus guidelines for the genetic diagnosis of alport syndrome
Pediatric Nephrology, 2019Co-Authors: Judy Savige, Francesca Ariani, Oliver Gross, Mirella Bruttini, Frances Flinter, Constantinos Deltas, Alessandra Renieri, Francesca Mari, Daniel P GaleAbstract:Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
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segregation of hematuria in thin basement membrane disease with haplotypes at the loci for alport syndrome
Kidney International, 2001Co-Authors: Mark Buzza, Diane Wilson, Judy SavigeAbstract:Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome. Background Inherited hematuria is common and is usually attributed to thin basement membrane disease (TBMD). The aim of this study was to determine how often hematuria in families with TBMD segregated with haplotypes at the chromosomal loci for autosomal recessive and X-linked Alport syndrome (COL4A3/COL4A4 and COL4A5, respectively). Methods The families of 22 individuals with TBMD on renal biopsy and with urinary glomerular red blood cell (RBC) counts of more than 50,000/mL were studied using phase-contrast microscopy of the urine and DNA microsatellite markers. Eighteen families had at least two members with hematuria. Results Hematuria segregated with or was consistent with segregation at the COL4A3/COL4A4 locus in eight (36%) families ( P P Conclusions Hematuria in families with TBMD commonly segregates with the COL4A3/COL4A4 locus and thus results from mutations in the same genes as autosomal recessive Alport syndrome. Sometimes TBMD may be confused with the carrier state for X-linked Alport syndrome. However, nearly half of the families in this study had hematuria that did not segregate with the loci for either autosomal recessive or X-linked Alport syndrome.
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Ocular manifestations of autosomal recessive Alport syndrome
Ophthalmic Genetics, 1997Co-Authors: Deb Colville, M. Morfis, John W. M. Agar, Judy Savige, J. Ellis, P. Kerr, R. FassetAbstract:Ocular abnormalities are common in X-linked Alport syndrome, but they have not been studied in patients with the rarer autosomal recessive disease. We have examined the eyes of a family with autosomal recessive Alport syndrome. Four of the eight offspring of a consanguineous marriage had renal failure and deafness by the age of 20 years. The diagnosis of Alport syndrome was confirmed on the ultrastructural demonstration of a lamellated glomerular basement membrane (GBM) in one affected family member. Autosomal recessive inheritance was suggested by the lack of linkage to the COL4A5/COL4A6 locus, and by linkage to the COL4A3/COL4A4 locus. All four affected family members had anterior lenticonus (or had had a lens replacement for this) and the three who were examined had a dot-and-fleck retinopathy. Neither of the two unaffected offspring who were examined nor the father had these abnormalities. The ocular manifestations of autosomal recessive Alport syndrome are probably identical to those for the X-linked...
Alessandra Renieri - One of the best experts on this subject based on the ideXlab platform.
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expert consensus guidelines for the genetic diagnosis of alport syndrome
Pediatric Nephrology, 2019Co-Authors: Judy Savige, Francesca Ariani, Oliver Gross, Mirella Bruttini, Frances Flinter, Constantinos Deltas, Alessandra Renieri, Francesca Mari, Daniel P GaleAbstract:Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
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Advances in Alport syndrome diagnosis using next generation sequencing
European Journal of Human Genetics, 2011Co-Authors: Alessandra Renieri, Laura Massella, Rosangela Artuso, Chiara Fallerini, Laura Dosa, Francesca Scionti, Maurizio Clementi, Guido Garosi, Maria Carmela Epistolato, Roberta ManciniAbstract:Alport syndrome is a hereditary nephropathy often associated with sensorineural hypoacusis and ocular abnormalities. Mutations in the COL4A5 gene cause X-linked Alport syndrome. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant Alport syndrome. The conventional mutation screening, performed by DHPLC and/or Sanger sequencing, is time consuming and has relatively high costs due to the absence of hot spots and to the high number of exons per gene: 51 (COL4A5), 48 (COL4A4), and 52 (COL4A3). Several months are usually necessary to complete the diagnosis, especially in cases with less informative pedigrees. To overcome these limitations, we designed a next generation sequencing protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA-sequencing platform (GS junior). The application of this technology allowed us to identify the second mutation in two Alport syndrome patients (p.Ser1147Phe in COL4A3 and p.Arg1682Trp in COL4A4) and to reconsider the diagnosis of Alport syndrome in a third patient. This study, therefore, illustrates the successful application of next generation sequencing to mutation screening of Mendelian disorders with locus heterogeneity.
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alport syndrome and leiomyomatosis the first deletion extending beyond COL4A6 intron 2
Pediatric Nephrology, 2011Co-Authors: Vera Uliana, Mirella Bruttini, Francesco Scolari, Ilaria Meloni, Elena Marcocci, Mafalda Mucciolo, Claudia Izzi, Carlo Manno, Francesca Mari, Alessandra RenieriAbstract:Alport syndrome (ATS) is a nephropathy characterized by the association of progressive hematuric nephritis with ultrastructural changes of the glomerular basement membrane (thinning, thickening, and splitting), sensorineural deafness, and variable ocular abnormalities (anterior lenticonus, macular flecks, and cataracts). The most common mode of transmission is X-linked inheritance, due to COL4A5 mutations. X-linked ATS is rarely associated with diffuse leiomyomatosis (DL), a benign hypertrophy of the visceral smooth muscle in gastrointestinal, respiratory, and female reproductive tracts. The ATS-DL complex is due to deletions that encompass the 5′ ends of the COL4A5 and COL4A6 genes and include the bidirectional promoter. In this paper, we described 3 ATS-DL cases, 2 familial and 1 sporadic bearing a deletion encompassing the 5′-end of both the COL4A5 and COL4A6 genes, as identified by multiplex ligation-dependent probe amplification (MLPA) analysis. The array-CGH technique allowed a better definition of deletion size, confirming that the proximal breakpoint was within COL4A6 intron 2 in 2 cases. Surprisingly, 1 case had a deletion extending proximally beyond exon 3 of COL4A6, as confirmed by qPCR analysis. This is the largest deletion reported to date that has been associated with ATS-DL and this case should lead us to reconsider the mechanisms that might be involved in the development of diffuse leiomyomatosis.
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Autosomal Alport Syndrome: a new model including both dominant and recessive inheritance
2010Co-Authors: Marcocci Elena, Alessandra RenieriAbstract:Alport syndrome (ATS) is a nephropathy characterized by the association of progressive hematuric nephritis with ultrastructural changes of the glomerular basement membrane (thinning, thickening and splitting), sensorineural deafness, and variable ocular abnormalities (anterior lenticonus, macular fleckes and cataracts). The most common mode of transmission is X-linked inheritance, due to COL4A5 mutations. X-linked ATS is rarely associated with diffuse leiomyomatosis (DL), a benign hypertrophy of the visceral smooth muscle in gastrointestinal, respiratory and female reproductive tracts. The ATSDL complex is due to deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes and include the bidirectional promoter. In this paper, we described three ATS-DL cases, two familial and one sporadic bearing a deletion encompassing 5’-end of both COL4A5 and COL4A6 genes, identified by MLPA analysis. Array-CGH technique allowed a better definition of deletion size confirming that the proximal breakpoint was within COL4A6 intron II in two cases. Surprisingly, one case had a deletion extending proximally beyond exon 3 of COL4A6, confirmed by qPCR analysis. This in the largest deletion reported to date associated with ATS-DL and this case should lead us to reconsider the mechanisms that may be involved in the development of diffuse leyomiomatosis.
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Deletion spanning the 5′ ends of both the COL4A5 and COL4A6 genes in a patient with Alport's syndrome and leiomyomatosis
Human Mutation, 2005Co-Authors: Alessandra Renieri, Mario De Marchi, Lucia Galli, M T Bassi, Marisa Giani, Jing Zhou, Andrea BallabioAbstract:Alport's syndrome is characterized clinically by a nonimmune glomerulopathy, often accompanied by sensorineural hearing loss and lens abnormalities, frequently due to mutations in the COL4A5 gene. The association of AS with diffuse leiomyomatosis, a benign proliferation of smooth muscle that occurs most often in the esophagus, trachea, and female genitalia, has been reported. Recently, a deletion involving both the COL4A5 and COL4A6 genes has been reported in four unrelated families. We report an additional case with Alport's syndrome associated with leiomyomatosis carrying a deletion of both COL4A5 and COL4A6 genes. A detailed characterization of the genomic region involved in the deletion event has been performed. Our results demonstrate that the deletion removed exon l of COL4A5 and exons l and 2 of COL4A6. © 1994 Wiley-Liss, Inc.