Evidence for Genetic Heterogeneity in Benign Familial Hematuria

Piccini, Monica; Casari, Giorgio; Zhou, Janhua; Bruttini, Mirella; Volti, S. Li; Ballabio, Andrea; Renieri, Alessandra

doi:10.1159/000013499

Cited by 42 publications

(25 citation statements)

References 15 publications

(20 reference statements)

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“…In contrast to these hypotheses, the results of this study showed a normal labeling of the α4(IV) and α3(IV) chain and, surprisingly, reduced labeling of α5(IV) along the GBM. Furthermore, the fact that our data indicated that the ratio of α5(IV) to α2(IV) varies strongly from one patient to another supports the hypothesis of Piccini et al [21]that TBMD is genetically heterogeneous.…”

Section: Discussionsupporting

confidence: 89%

“…These data therefore suggest the possibility that the thinning of the GBM evident in TBMD might depend upon the character of the α5(IV) chain. Some investigators [6, 21]have also speculated that inherited abnormalities might account for the histological changes in the GBM. We, therefore, hypothesized the association of the α5(IV) chain with the attenuation of the GBM and analyzed the relationship between the signal intensity of the α5(IV) chain and the thickness of the GBM in each patient with TBMD but, somewhat unexpectedly, found no significant correlation.…”

Section: Discussionmentioning

confidence: 99%

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Quantitative Analysis of Glomerular Type IV Collagen Alpha3–5 Chain Expression in Children with Thin Basement Membrane Disease

Ueda

Nakajima

Akazawa

et al. 2002

Nephron

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Thin basement membrane disease (TBMD) and Alport syndrome, two forms of childhood nephritis, have generally been considered to be hereditary diseases. In Alport syndrome, several reports have demonstrated pathogenic mutations of the genes encoding type IV collagen α3, 4 and/or 5 chain [α3, 4 and/or 5(IV)]. Previous immunohistochemical studies indicated that these antigens were absent from the glomerular basement membrane (GBM) in Alport syndrome, whilst a normal labeling pattern was maintained in TBMD. In order to understand the role of the α3, 4 and/or 5(IV) antigens in TBMD, we used confocal laser scanning microscopy (CLSM) to examine cryosections of renal biopsies from 12 children with TBMD and 11 control children with IgA nephropathy (IgAN) without proteinuria. All tissue sections were stained with a mixture of FITC-conjugated rat monoclonal antibodies directed against human α3(IV), α4(IV) or α5(IV) and a Texas red-conjugated rat monoclonal antibody raised against human α2(IV). CLSM was performed and quantitative analysis of the ratio of the staining signal for α3(IV), α4(IV) or α5(IV) to α2(IV) [α3(IV), α4(IV) or α5(IV)/α2(IV)] along the GBM was determined. The average number of pixels for α3(IV), α4(IV) or α5(IV)/α2(IV) was 3.52 ± 1.49, 3.54 ± 1.25 and 1.09 ± 0.49 in TBMD and 3.62 ± 1.46, 3.99 ± 1.53 and 1.77 ± 0.47 in control subjects, respectively. Statistical analysis indicated that α5(IV)/α2(IV) ratio was significantly lower (p < 0.01) in children with TBMD compared to controls. These findings raise the possibility that TBMD might be caused by an abnormality of the α5(IV) antigen along the GBM.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Glomerular Type IV Collagen Alpha3–5 Chain Expression in Children with Thin Basement Membrane Disease

Ueda

Nakajima

Akazawa

et al. 2002

Nephron

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“…Although the number of cases of BFH is limited in our series, this finding suggests that there is no genetic heterogeneity in BFH and that families that have been described with hematuria that does not segregate with the COL4A3/COL4A4 locus 34,35 can be explained by coincidental hematuria in family members rather than a novel locus for BFH.…”

Section: Discussionmentioning

confidence: 64%

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Morinière¹,

Dahan

Hilbert

et al. 2014

Journal of the American Society of Nephrology

135

131

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Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the webbased sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.

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“…Many families with TBMN do not show linkage to the COL4A3/COL4A4 or COL4A5 loci (98,99). This may be explained by several factors.…”

Section: -Terminus (B) Three Chains Form Triple-helical Molecules Thmentioning

confidence: 97%

Thin Basement Membrane Nephropathy

Tryggvason¹,

Patrakka²

2006

Journal of the American Society of Nephrology

106

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Evidence for Genetic Heterogeneity in Benign Familial Hematuria

Cited by 42 publications

References 15 publications

Quantitative Analysis of Glomerular Type IV Collagen Alpha3–5 Chain Expression in Children with Thin Basement Membrane Disease

Quantitative Analysis of Glomerular Type IV Collagen Alpha3–5 Chain Expression in Children with Thin Basement Membrane Disease

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Thin Basement Membrane Nephropathy

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