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A Mutation in the TRPC6 Cation Channel Causes Familial Focal

Few prospective, randomized controlled clinical trials address the diagnosis and management of patientswith Alportsyndrome or thinbasement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18recommendationsarebased onLevel D (Expert opinion withoutexplicitcritical appraisal,orbasedonphysiology, bench research, or first principles—NationalHealth Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees—U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstrationofitsmodeofinheritance;theneedtoidentifyandfollowallaffectedmembersofa family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and considerationofgenetictestingtoexcludeX-linkedAlportsyndromeinsomeindividualswith thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In this Review, we discuss the latest basic and clinical research on Alport syndrome, focusing on the roles of podocyte pathology and the extracellular matrix. We also highlight early diagnosis and treatment options for young patients with this disorder.

Alport syndrome—insights from basic and clinical research

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning Typically, these features do not affect vision or, in the case of lenticonus, are correctable In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease Sometimes, ophthalmic features suggest the mode of inheritance A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive It also detects complications, such as macular hole, for which new treatments are emerging

Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance

Background Alport syndrome is a clinically heterogeneous, progressive nephropathy caused by mutations in collagen IV genes, namely COL4A3 and COL4A4 on chromosome 2 and COL4A5 on chromosome X. The wide phenotypic variability and the presence of incomplete penetrance suggest that a simple Mendelian model cannot completely explain the genetic control of this disease. Therefore, we explored the possibility that Alport syndrome is under digenic control. Methods Using massively parallel sequencing, we identified 11 patients who had pathogenic mutations in two collagen IV genes. For each proband, we ascertained the presence of the same mutations in up to 12 members of the extended family for a total of 56 persons studied. Results Overall, 23 mutations were found. Individuals with two pathogenic mutations in different genes had a mean age of renal function deterioration intermediate with respect to the autosomal-dominant form and the autosomal-recessive one, in line with molecule stoichiometry of the disruption of the type IV collagen triple helix. Conclusions Segregation analysis indicated three possible digenic segregation models: (i) autosomal inheritance with mutations on different chromosomes, resembling recessive inheritance (five families); (ii) autosomal inheritance with mutations on the same chromosome resembling dominant inheritance (two families) and (iii) unlinked autosomal and X-linked inheritance having a peculiar segregation (four families). This pedigree analysis provides evidence for digenic inheritance of Alport syndrome. Clinical geneticists and nephrologists should be aware of this possibility in order to more accurately assess inheritance probabilities, predict prognosis and identify other family members at risk.

/pdf/evidence-of-digenic-inheritance-in-alport-syndrome-32trmcbvl5.pdf

Evidence of digenic inheritance in Alport syndrome

Thin-basement-membrane nephropathy (TBMN) is characterized by persistent dysmorphic hematuria, and the presence of proteinuria is a risk factor for renal impairment. TBMN is often due to mutations in the COL4A3 and COL4A4 genes, and this study determined whether additional mutations in genes encoding other structures in the glomerular filtration barrier contributed to the development of proteinuria. Fifty-six unrelated individuals with TBMN including 18 (32%) with proteinuria ≥ 300 mg/L and ten (18%) with proteinuria ≥ 500 mg/L were studied. Deoxyribonucleic acid (DNA) was screened for NPHS2 mutations and variants (R138Q and P375L) using single-stranded conformational analysis (SSCA) and for the R229Q mutation by sequencing. DNA was also screened for ACTN4 mutations. R229Q was more common in patients with TBMN and proteinuria ≥ 500 mg/L (p A, R224H) was identified in one patient with proteinuria 700 mg/L. No other NPHS2 variants correlated with proteinuria, and no ACTN4 mutations were found. Individuals with TBMN and R229Q are carriers of the autosomal recessive forms of both Alport syndrome and familial focal segmental glomerulosclerosis (FSGS). The early demonstration of R229Q in individuals with TBMN may indicate those at increased risk of proteinuria and renal impairment.

The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy

Background and objectives: Previous studies of X-linked Alport syndrome demonstrated that “severe” COL4A5 mutations (large deletions and rearrangements, nonsense and frame-shift mutations, and glycine substitutions in the carboxy-terminal residues) were associated with early-onset renal failure, hearing loss, and lenticonus in affected male patients. This study examined whether severe mutations also resulted in the typical perimacular dot-and-fleck retinopathy.

Design, setting, participants, & measurements: Twenty unrelated families with X-linked Alport syndrome were studied for the causative mutation in the COL4A5 gene. Nineteen affected male and 22 affected female individuals aged at least 14 yr from these families were examined for clinical and, in particular, ophthalmologic features.

Results: Nineteen pathogenic mutations were identified in the COL4A5 gene in the 20 families using a thermal melt analyzer (HRM RotorGene 6000; Corbett) or direct sequencing of hair root or skin fibroblast cDNA. Fifteen mutations were classified severe and four as moderate. Severe mutations were associated with the central dot-and-fleck Alport retinopathy in male individuals (P = 0.0256) in addition to early-onset renal failure, hearing loss, and lenticonus (P = 0.0009, 0.009, and 0.009, respectively). Severe mutations did not correlate with clinical features in female individuals.

Conclusions: Severe mutations in male individuals with X-linked Alport syndrome are associated with the perimacular dot-and-fleck retinopathy. Furthermore, the retinopathy indicates that male individuals are at increased risk for renal failure before the age of 30 (P = 0.0007).

Alport Retinopathy Results from “Severe” COL4A5 Mutations and Predicts Early Renal Failure

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The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy

Alport Retinopathy Results from “Severe” COL4A5 Mutations and Predicts Early Renal Failure