Genetics of Classic Alport's Syndrome

Flinter, Frances; Cameron, J. S.; Chantler, C; Houston, I. B.; Bobrow, Martin

doi:10.1016/s0140-6736(88)90753-2

Cited by 189 publications

(128 citation statements)

References 23 publications

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“…[1][2][3][4] AS is caused by defects in type IV collagen, a major component of basement membranes. 5 Six ␣(IV) collagen chains, ␣1(IV) to ␣6(IV), have been identified so far in mammals.…”

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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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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“…These features are also seen in AS, where renal disease generally manifests as recurrent microscopic or gross hematuria associated with high frequency sensorineural hearing loss and/or ocular anomalies and progression to renal failure usually occurs, at least in males, by the fifth decade (5). The classic AS phenotype, however, shows considerable phenotypic heterogeneity in the age of onset of ESRD, and the severity of auditory and renal features may not correlate (11,28). The renal histology in AS can also be variable and involves both glomerular and tubulointerstitial abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to FSGS, AS is associated with hematuria, deafness, and characteristic ultrastructural abnormalities of the glomerular basement membrane (GBM) (5,10). AS also displays considerable phenotypic and genetic heterogeneity with the classic X-linked forms accounting for almost 85% of the cases, and the remaining 15% of cases showing autosomal inheritance (11)(12)(13)(14). X-linked AS (MIM 301050) is associated with type IV collagen alpha 5 chain (COL4A5) mutations, while mutations in alpha 3 chain (COL4A3) and alpha 4 chain (COL4A4) genes, located on chromosome 2q35-q37, have been found in cases of both autosomal recessive (MIM 203780) and dominant (MIM 104200) AS (12)(13)(14)(15)(16).…”

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confidence: 99%

Autosomal Dominant Progressive Nephropathy with Deafness

Prakash¹,

Chung²,

Sinha³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are two major causes of end-stage renal disease (ESRD). A few families with autosomal dominant FSGS have been reported with linkage to chromosome 19q13 or 11q22, while AS is usually linked to mutations in type IV collagen (COL4) subunit genes. A phenotype resembling AS may also be seen with myosin heavy chain-9 (MYH9) gene mutations. This study ascertained a multigeneration family (CHP-177) with clinical aspects of both FSGS and AS where we identified a new locus for the trait. A genome-wide scan was performed with 400 markers, and fine mapping was performed for chromosome 11 markers. Data were analyzed by GENEHUNTER and VITESSE under various models. CHP-177 is a 39-member kindred residing near New Delhi, India, with seven affecteds and showed male-to-male transmission. Two members had ESRD. Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the affecteds also had sensorineural deafness, which involved both low and high frequency in some members. The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores: Ϫ6.1 and Ϫ4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage. A significant evidence of linkage was observed for 11q24 region, with a multipoint LOD (z-score) of 3.2 for marker D11S4464 at ϭ 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype.

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“…X-linked form: highly dependent on fulfillment of the clinical criteria for Alport syndrome 4 and may be supported by immunohistochemical findings in a kidney and/or skin biopsy. Above 80% in families fulfilling three or more diagnostic criteria.…”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 93%

“…Higher in families with obvious X-linked inheritance, and higher in males than in females. 5 Autosomal recessive form: highly dependent on fulfilment of the clinical criteria for Alport syndrome 4 and may be supported by abnormal immunohistochemical findings in a kidney biopsy, and normal immunohistochemical findings in a skin biopsy. Above 80% in families fulfilling three or more diagnostic criteria.…”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 99%