The clinical spectrum of type IV collagen mutations

Lemmink, Henny H.; Schröder, Cornelis H.; Monnens, L.A.H.; Smeets, H.J.M.

doi:10.1002/(sici)1098-1004(1997)9:6<477::aid-humu1>3.0.co;2-#

Cited by 158 publications

(70 citation statements)

References 109 publications

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“…This may be explained by several factors. A high rate of de novo mutations has been shown in the COL4A5 gene in X-linked Alport syndrome, and this might be the case in COL4A3 and COL4A4 genes as well (100). Incomplete penetrance of hematuria in heterozygous carriers has also been reported (101), and this can influence linkage analyses.…”

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

confidence: 99%

Thin Basement Membrane Nephropathy

Tryggvason¹,

Patrakka²

2006

Journal of the American Society of Nephrology

108

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

confidence: 99%

Thin Basement Membrane Nephropathy

Tryggvason¹,

Patrakka²

2006

Journal of the American Society of Nephrology

108

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“…The disease is caused by mutations in type IV collagen genes (1,(4)(5)(6). Eighty-five percent of Alport families have an X-linked (COL4A5 gene) and 15% an autosomal-recessive (COL4A3 or COL4A4 genes) pattern of inheritance (1,(7)(8)(9)(10). Female heterozygous X-linked Alport carriers show a large interand intrafamilial variability of the clinical course and a more favorable prognosis (11,12).…”

Section: Introductionmentioning

confidence: 99%

Outcomes of Male Patients with Alport Syndrome Undergoing Renal Replacement Therapy

Temme¹,

Kramer²,

Jager³

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Patients with the hereditary disease Alport syndrome commonly require renal replacement therapy (RRT) in the second or third decade of life. This study compared age at onset of RRT, renal allograft, and patient survival in men with Alport syndrome receiving various forms of RRT (peritoneal dialysis, hemodialysis, or transplantation) with those of men with other renal diseases.Design, setting, participants, & measurements Patients with Alport syndrome receiving RRT identified from 14 registries in Europe were matched to patients with other renal diseases. A linear spline model was used to detect changes in the age at start of RRT over time. Kaplan-Meier method and Cox regression analysis were used to examine patient and graft survival.

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“…6 -11 COL4A5 mutations lead to the most common form of AS which is X-linked, whereas COL4A3 and COL4A4 mutations are responsible for the autosomal recessive forms. [12][13][14][15][16][17][18][19] The primary structure of the six ␣(IV) chains is very similar. Each is characterized by an ϳ25-residue noncollagenous domain at the amino terminus, an ϳ1400 residue collagenous domain of Gly-X-Y repeats (in which X is frequently proline and Y is frequently hydroxyproline), that forms, in association with two other chains, the triple helix, and an ϳ230-residue noncollagenous (NC1) domain at the carboxyl terminus.…”

mentioning

confidence: 99%

“…28 -31 The presence of cysteine-rich ␣3(IV) and ␣4(IV) chains, forming with ␣5(IV) a network containing loops and supercoiled triple helices stabilized by disulfide bonds between the chains, seems to be important with regards to the longterm stability of the GBM and its role as a filter. 26,32 Despite the increasing number of AS mutations reported in the literature [12][13][14][15][16][17][18][19] and the existence of AS animal models, [33][34][35][36][37] several questions regarding the consequences of AS mutations on the collagen organization within the GBM and the mechanisms responsible for the progressive development of AS nephropathy remain unanswered. A striking feature observed in the majority of AS is the absence of all three ␣3(IV), ␣4(IV), and ␣5(IV) chains within the GBM although only one of these chains is actually mutated.…”

mentioning

confidence: 99%

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the ␣5 chains of type IV collagen in basement membranes. This is associated with the absence of the ␣3(IV) and ␣4(IV) chains and increased amounts of ␣1(IV) and ␣2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the ␣3 chain of type IV collagen was present in the podocytes of all patients. Finally, the ␣1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of ␣3(IV) to ␣5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

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The clinical spectrum of type IV collagen mutations

Cited by 158 publications

References 109 publications

Thin Basement Membrane Nephropathy

Thin Basement Membrane Nephropathy

Outcomes of Male Patients with Alport Syndrome Undergoing Renal Replacement Therapy

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

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