The Experts below are selected from a list of 1677 Experts worldwide ranked by ideXlab platform
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, Gina Parziale, Judy Savige, Oliver Gross, Frances Flinter, 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, Constantinos Deltas, Oliver Gross, Mirella Bruttini, Francesca Mari, Frances Flinter, Jie Ding, Alessandra Renieri, 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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x linked and autosomal recessive alport syndrome pathogenic variant features and further genotype phenotype correlations
PLOS ONE, 2016Co-Authors: Judy Savige, Helen Storey, Hae Il Cheong, Hee Gyung Kang, Eujin Park, Pascale Hilbert, Anton V Persikov, Carmen Torresfernandez, Roser Torra, Jens Michael HertzAbstract:Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure occurred sooner with two non-missense variants (p = 0.08, and p = 0.01 respectively). Thus DNA variant characteristics that predict age at renal failure appeared to be the same for all three Alport genes. Founder mutations (with the pathogenic variant in at least 5 apparently- unrelated individuals) were not necessarily associated with a milder phenotype. This study illustrates the benefits when routine diagnostic laboratories share and analyse their data.
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Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?
Pediatric Nephrology, 2007Co-Authors: Ke Wei Zhang, Stephen Tonna, Yan Yan Wang, Kesha Rana, Smitha Padavarat, Judy SavigeAbstract:Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans ( COL4A5 ) and mice ( COL4A1 ). This study examined whether COL4A1 / COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3 / COL4A4 , were examined for linkage to COL4A1 / COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations ( n =23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1 / COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1 / COL4A2 does not represent a further major genetic locus for TBMN.
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do mutations in col4a1 or col4a2 cause thin basement membrane nephropathy tbmn
Pediatric Nephrology, 2007Co-Authors: Ke Wei Zhang, Stephen Tonna, Yan Yan Wang, Kesha Rana, Smitha Padavarat, Judy SavigeAbstract:Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans (COL4A5) and mice (COL4A1). This study examined whether COL4A1/COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3/COL4A4, were examined for linkage to COL4A1/COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations (n=23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1/COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1/COL4A2 does not represent a further major genetic locus for TBMN.
Alessandra Renieri - One of the best experts on this subject based on the ideXlab platform.
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Clinical and genetic features of the Alport 'syndromes'
Giornale italiano di nefrologia : organo ufficiale della Società italiana di nefrologia, 2020Co-Authors: Chiara Pescucci, Rossella Caselli, Elisa Scala, Mirella Bruttini, Francesca Mari, I. Longo, Alessandra RenieriAbstract:Alport syndrome (ATS) is a clinically and genetically heterogeneous progressive nephropathy often associated with deafness and/or ocular lesions. The histological aspect is characterized by thinning, thickening and splitting of the glomerular basement membrane (GBM). Alport syndrome is caused by mutations in COL4A3 gene (type IV collagen, alfa-3 chain), or COL4A4 gene (type IV collagen, alfa-4 chain) or COL4A5 gene (type IV collagen, alfa-5 chain) genes. Alport syndrome accounts for 1-2% of renal failure cases in Europe, and for 2-3% of transplanted patients in United States. This review focuses on the three types of Alport syndrome which differ in the clinical progression and in the mode of inheritance. The common X-linked form is caused by mutations in the COL4A5 gene and it accounts for 85% of cases. The autosomal dominant and the autosomal recessive forms are caused by mutations in either COL4A3 or COL4A4 genes. The autosomal recessive form which is responsible for the 10-15% of Alport cases, has been known since several years. On the contrary, the autosomal dominant form has only recently been identified in some families. Furthermore, this review will focus on the difficulties encountered during the genetic counselling related to the differential diagnosis between Alport syndrome and Thin Basement Membrane Disease (TBMD). We will report direct experiences of our group showing the difficulties to give an exact prognosis and a correct recurrence risk to the family.
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expert consensus guidelines for the genetic diagnosis of alport syndrome
Pediatric Nephrology, 2019Co-Authors: Judy Savige, Francesca Ariani, Constantinos Deltas, Oliver Gross, Mirella Bruttini, Francesca Mari, Frances Flinter, Jie Ding, Alessandra Renieri, 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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alport syndrome a unified classification of genetic disorders of collagen iv α345 a position paper of the alport syndrome classification working group
Kidney International, 2018Co-Authors: Clifford E Kashtan, Michelle N Rheault, Laurence Heidet, Laura Massella, Guido Garosi, Koichi Nakanishi, Kandai Nozu, Jie Ding, Alessandra Renieri, Fang WangAbstract:Mutations in the genes COL4A3, COL4A4 , and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment.
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alport syndrome and leiomyomatosis the first deletion extending beyond col4a6 intron 2
Pediatric Nephrology, 2011Co-Authors: Vera Uliana, Mirella Bruttini, Francesca Mari, Francesco Scolari, Ilaria Meloni, Elena Marcocci, Mafalda Mucciolo, Claudia Izzi, Carlo Manno, 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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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, Jing Zhou, Lucia Galli, M T Bassi, Marisa Giani, 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.
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, Jing Zhou, Lucia Galli, M T Bassi, Marisa Giani, 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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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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line 1 elements at the sites of molecular rearrangements in alport syndrome diffuse leiomyomatosis
American Journal of Human Genetics, 1999Co-Authors: Yoav Segal, Bernard Peissel, Mario De Marchi, Andrea Ballabio, Alessandra Renieri, Jing ZhouAbstract:Summary 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.
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high mutation detection rate in the COL4A5 collagen gene in suspected alport syndrome using pcr and direct dna sequencing
Journal of The American Society of Nephrology, 1998Co-Authors: Paula Martin, Jens Michael Hertz, N Heiskari, Aki Leinonen, T Tumelius, Martin C Gregory, Curtis L Atkin, D. Barker, Jing Zhou, Unnur StyrkarsdottirAbstract:Approximately 85% of patients with Alport syn- drome (hereditary nephritis) have been estimated to have mu- tations in the X chromosomab COL4AS collagen gene; the remaining cases are autosomal with mutations in the COL4A3 or COL4A4 genes located on chromosome 2. In the present work, the promoter sequence and previously unknown intron sequences flanking exons 2 and 37 of COL4AS were deter- mined. Furthermore, intron sequences flanking the other 49 exons were expanded from 35 to 190 to facilitate mutation analysis of the gene. Using this information, all S 1 exons and the promoter region were PCR-ampbified and sequenced from DNA of SO randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mu- tation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Al- though it could not be determined whether the remaining seven cases (14%) were autosomab or X chromosome-linked, it is likely that some of them were autosomal. It is concluded that PCR amplification and direct DNA sequencing of the promoter
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novel COL4A5 col4a6 deletions and further characterization of the diffuse leiomyomatosis alport syndrome dl as locus define the dl critical region
Cytogenetic and Genome Research, 1997Co-Authors: Laurence Heidet, Frances Flinter, Jing Zhou, L Cohensolal, Eileen Boye, Paul S Thorner, M J Kemper, Albert David, Larget L Piet, X ZhangAbstract:Diffuse leiomyomatosis (DL) with Alport syndrome (AS) has been shown to be associated with contiguous gene deletions of the COL4A5 and COL4A6 genes, with the COL4A6 breakpoint of the deletions invariably located in the large intron 2 of the gene. We describe four YAC clones covering the locus and a refined restriction map of the entire COL4A6 gene. These resources have allowed us to make a precise estimate of the size of COL4A6 introns 2 and 3, as well as the size of the gene itself. We also describe five novel deletions which, in conjunction with previous reports, allow the definition of a 90-kb critical region in which to search for a gene or other entity involved in the pathogenesis of DL.
Yan Yan Wang - One of the best experts on this subject based on the ideXlab platform.
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Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?
Pediatric Nephrology, 2007Co-Authors: Ke Wei Zhang, Stephen Tonna, Yan Yan Wang, Kesha Rana, Smitha Padavarat, Judy SavigeAbstract:Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans ( COL4A5 ) and mice ( COL4A1 ). This study examined whether COL4A1 / COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3 / COL4A4 , were examined for linkage to COL4A1 / COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations ( n =23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1 / COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1 / COL4A2 does not represent a further major genetic locus for TBMN.
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do mutations in col4a1 or col4a2 cause thin basement membrane nephropathy tbmn
Pediatric Nephrology, 2007Co-Authors: Ke Wei Zhang, Stephen Tonna, Yan Yan Wang, Kesha Rana, Smitha Padavarat, Judy SavigeAbstract:Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans (COL4A5) and mice (COL4A1). This study examined whether COL4A1/COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3/COL4A4, were examined for linkage to COL4A1/COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations (n=23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1/COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1/COL4A2 does not represent a further major genetic locus for TBMN.
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thin basement membrane nephropathy
Kidney International, 2003Co-Authors: Judy Savige, Mark Buzza, Stephen Tonna, Kesha Rana, Hayat Dagher, Yan Yan WangAbstract:Thin basement membrane nephropathy. Thin basement membrane nephropathy (TBMN) is the most common cause of persistent glomerular bleeding in children and adults, and occurs in at least 1% of the population. Most affected individuals have, in addition to the hematuria, minimal proteinuria, normal renal function, a uniformly thinned glomerular basement membrane (GBM) and a family history of hematuria. Their clinical course is usually benign. However, some adults with TBMN have proteinuria>500mg/day or renal impairment. This is more likely in hospital-based series of biopsied patients than in the uninvestigated, but affected, family members. The cause of renal impairment in TBMN is usually not known, but may be due to secondary focal segmental glomerulosclerosis (FSGS) or immunoglobulin A (IgA) glomerulonephritis, to misdiagnosed IgA disease or X-linked Alport syndrome, or because of coincidental disease. About 40% families with TBMN have hematuria that segregates with the COL4A3/COL4A4 locus, and many COL4A3 and COL4A4 mutations have now been described. These genes are also affected in autosomal-recessive Alport syndrome, and at least some cases of TBMN represent the carrier state for this condition. Families with TBMN in whom hematuria does not segregate with the COL4A3/COL4A4 locus can be explained by de novo mutations, incomplete penetrance of hematuria, coincidental hematuria in family members without COL4A3 or COL4A4 mutations, and by a novel gene locus for TBMN. A renal biopsy is warranted in TBMN only if there are atypical features, or if IgA disease or X-linked Alport syndrome cannot be excluded clinically. In IgA disease, there is usually no family history of hematuria. X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen α3(IV), α4(IV), and α5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation. Technical difficulties in the demonstration and interpretation of COL4A3 and COL4A4 mutations mean that mutation detection is not used routinely in the diagnosis of TBMN.
Douglas B Gould - One of the best experts on this subject based on the ideXlab platform.
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COL4A1 Mutations Cause Neuromuscular Disease with Tissue-Specific Mechanistic Heterogeneity.
American Journal of Human Genetics, 2019Co-Authors: Cassandre Labelle-dumais, Genki Hayashi, Vera Schuitema, Kendall Hoff, Wenhui Gong, Erik M. Ullian, Peter Oishi, Marta Margeta, Douglas B GouldAbstract:Collagen type IV alpha 1 and alpha 2 chains form heterotrimers ([α1(IV)]2α2(IV)) that represent a fundamental basement membrane constituent. Dominant COL4A1 and COL4A2 mutations cause a multisystem disorder that is marked by clinical heterogeneity and variable expressivity and that is generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular involvement. Despite the fact that muscle pathology is reported in up to one-third of individuals with COL4A1 and COL4A2 mutations and in animal models with mutations in COL4A1 and COL4A2 orthologs, the pathophysiological mechanisms underlying COL4A1-related myopathy are unknown. In general, mutations are thought to impair [α1(IV)]2α2(IV) secretion. Whether pathogenesis results from intracellular retention, extracellular deficiency, or the presence of mutant proteins in basement membranes represents an important gap in knowledge and a major obstacle for developing targeted interventions. We report that Col4a1 mutant mice develop progressive neuromuscular pathology that models human disease. We demonstrate that independent muscular, neural, and vascular insults contribute to neuromyopathy and that there is mechanistic heterogeneity among tissues. Importantly, we provide evidence of a COL4A1 functional subdomain with disproportionate significance for tissue-specific pathology and demonstrate that a potential therapeutic strategy aimed at promoting [α1(IV)]2α2(IV) secretion can ameliorate or exacerbate myopathy in a mutation-dependent manner. These data have important translational implications for prediction of clinical outcomes based on genotype, development of mechanism-based interventions, and genetic stratification for clinical trials. Collectively, our data underscore the importance of the [α1(IV)]2α2(IV) network as a multifunctional signaling platform and show that allelic and tissue-specific mechanistic heterogeneities contribute to the variable expressivity of COL4A1 and COL4A2 mutations.
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use of sodium 4 phenylbutyrate to define therapeutic parameters for reducing intracerebral hemorrhage and myopathy in col4a1 mutant mice
Disease Models & Mechanisms, 2018Co-Authors: Genki Hayashi, Cassandre Labelledumais, Douglas B GouldAbstract:Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers that constitute a major component of nearly all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that includes variable cerebrovascular and skeletal muscle manifestations. The pathogenicity of COL4A1 and COL4A2 mutations is generally attributed to impaired secretion into basement membranes. Sodium 4-phenylbutyrate (4PBA) is an FDA-approved drug that promotes mutant heterotrimer secretion in vitro and in vivo . Here, we use different 4PBA treatment paradigms to define therapeutic parameters for preventing cerebrovascular and muscular pathologies in Col4a1 mutant mice. We show efficacy of long-term 4PBA treatment in reducing the severity of intracerebral hemorrhages (ICH) in Col4a1 mutant mice aged up to 8 months. In addition, we demonstrate that maximal efficacy of 4PBA on ICH and myopathy was achieved when treatment was initiated prenatally, whereby even transient 4PBA administration had lasting benefits after being discontinued. Importantly, postnatal treatment with 4PBA also reduced ICH and skeletal myopathy severities in Col4a1 mutant mice, which has significant clinical implications for patients with COL4A1 and COL4A2 mutations.
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Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
Scientific Reports, 2016Co-Authors: Marcel V. Alavi, Bradley Pawlikowski, Manana Kvezereli, Jacque L. Duncan, Richard T. Libby, Simon W. M. John, Douglas B GouldAbstract:Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Muller cells and increased expression of pro-angiogenic factors in retinas from Col4a1(+/Δex41)mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes.
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Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention
Circulation, 2015Co-Authors: Marion Jeanne, Jeff Jorgensen, Douglas B GouldAbstract:Background—Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment. Methods and Results—Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small-vessel disease, recurrent hemorrhagic strokes, and age-related macroangiopathy. We showed that allelic heterogeneity, genetic context, and environmental factors such as intense exercise or anticoagulant medication modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endo...
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allelic heterogeneity contributes to variability in ocular dysgenesis myopathy and brain malformations caused by col4a1 and col4a2 mutations
Human Molecular Genetics, 2014Co-Authors: Cassandre Labelledumais, Marion Jeanne, William Kauffman, Jennifer M Allen, Jack Favor, Douglas B GouldAbstract:Collagen type IV alpha 1 and 2 (COL4A1 and COL4A2) are present in nearly all basement membranes. COL4A1 and COL4A2 mutations are pleiotropic, affecting multiple organ systems to differing degrees, and both genetic-context andenvironmentalfactorsinfluencethisvariableexpressivity.Here,we reportimportant phenotypic and molecular differences in an allelic series of Col4a1 and Col4a2 mutant mice that are on a uniform genetic background.WeevaluatedthreeorganscommonlyaffectedbyCOL4A1andCOL4A2mutationsanddiscovered allelic heterogeneity in the penetrance and severity of ocular dysgenesis, myopathy and brain malformations. Similarly, we show allelic heterogeneity in COL4A1 and COL4A2 biosynthesis. While most mutations that we examined caused increased intracellular and decreased extracellular COL4A1 and COL4A2, we identified three mutations with distinct biosynthetic signatures. Reduced temperature or presence of 4-phenylbutyrate amelioratedbiosyntheticdefectsinprimarycelllinesderivedfrommutantmice.Together,ourdatademonstrate the effects and clinical implications of allelic heterogeneity in Col4a1 -a ndCol4a2-related diseases. Understanding allelic differences will be valuable for increasing prognostic accuracy and for the development of therapeutic interventions that consider the nature of the molecular cause in patients with COL4A1 and COL4A2 mutations.