Co-Inheritance of Functional Podocin Variants with Heterozygous Collagen IV Mutations Predisposes to Renal Failure

Stefanou, Charalambos; Pieri, Myrtani; Savva, Isavella; Γεωργίου, Γεωργία; Pierides, Alkis; Voskarides, Konstantinos; Deltas, Constantinos

doi:10.1159/000432406

Cited by 24 publications

(20 citation statements)

References 39 publications

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“…This fact supports the use of LOAN as an alternative term to describe patients with thin basement membranes who can be complicated by proteinuria and decline of kidney function on long follow up, perhaps with the effect of genetic modifiers . For 3 such putative modifiers (2 in the NPHS2 gene [podocin] and 1 in the NEPH3 gene [filtrin]) co‐inherited with a COL4A3 mutation, functional cell culture studies were also supportive . In the present cohort none of the patients examined carried a high risk modifier allele, most probably due to their low population frequency.…”

Section: Discussionsupporting

confidence: 79%

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

et al. 2017

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Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

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Section: Discussionsupporting

confidence: 79%

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

et al. 2017

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“…Mutation NPHS2 ‐p.Arg229Gln was previously linked to steroid‐resistant nephrotic syndrome, a highly heterogeneous autosomal‐recessive nephropathy. In functional cell culture experiments, the alternative variant proteins impaired the interaction with other slit diaphragm partners and interfered with normal trafficking, demonstrating perinuclear staining . More recently we reported on the putative predisposing role of a variant in the NEPH3 gene (filtrin), also a component of the podocyte slit diaphragm .…”

Section: Primary Mutations and Genetic Modifiers As Examples Of Pseudmentioning

confidence: 84%

“…The 2 patients marked with an (×) symbol had exhibited VUR in childhood. WT: normal; COL4A3 :1334G/E: heterozygous for COL4A3 ‐p.Gly1334Gln; NPHS2 : 229R/Q, heterozygous for NPHS2 ‐p.Arg229Gln (reproduced with permission from Reference)…”

Section: Primary Mutations and Genetic Modifiers As Examples Of Pseudmentioning

confidence: 99%

Digenic inheritance and genetic modifiers

Deltas

2018

Clinical Genetics

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Digenic inheritance (DI) concerns pathologies with the simplest form of multigenic etiology, implicating more than 1 gene (and perhaps the environment). True DI is when biallelic or even triallelic mutations in 2 distinct genes, in cis or in trans, are necessary and sufficient to cause pathology with a defined diagnosis. In true DI, a heterozygous mutation in each of 2 genes alone is not associated with a recognizable phenotype. Well-documented diseases with true DI are so far rare and follow non-Mendelian inheritance. DI is also encountered when by serendipity, pathogenic mutations responsible for 2 distinct disease entities are co-inherited, leading to a mixed phenotype. Also, we can consider many true monogenic Mendelian conditions, which show impressively broad spectrum of phenotypes due to pseudo-DI, as a result of co-inheriting genetic modifiers (GMs). I am herewith reviewing examples of GM and embark on presenting some recent notable examples of true DI, with wider discussion of the literature. Undeniably, the advent of high throughput sequencing is bound to unravel more patients suffering with true DI conditions and elucidate many important GM, thus impacting precision medicine.

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“…More recently, a second NPHS2 variant, p.Glu237Gln, was also shown to predispose TBMN patients to severe kidney function decline on long follow-up. This work was accompanied by functional studies demonstrating altered localization of podocin and nephrin in transfected cultured podocytes [48]. …”

Section: The Spectrum Of Col4nmentioning

confidence: 99%

Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life

Deltas

Savva²,

Voskarides³

et al. 2015

Nephron

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Collagen IV nephropathies (COL4Ns) comprise benign familial microscopic hematuria, thin basement membrane nephropathy (TBMN), X-linked Alport syndrome (AS) and also autosomal recessive and dominant AS. Apart from the X-linked form of AS, which is caused by hemizygous mutations in the COL4A5 gene, the other entities are caused by mutations in the COL4A3 or COL4A4 genes. The diagnosis of these conditions used to be based on clinical and/or histological findings of renal biopsies, but it is the new molecular genetics approach that revolutionised their investigation and proved particularly instrumental, especially, in many not so clear-cut cases. More recently, the spectrum of COL4N has expanded to include late onset focal segmental glomerulosclerosis (FSGS) that develops on top of TBMN in later life. Also, other reports showed that some patients with a primary diagnosis of familial FSGS proved to have variants in COL4 genes. In the presence of a renal biopsy picture of FSGS and in the absence of either electron microscopy studies or molecular genetic studies that point to TBMN and COL4N, the patient and his family may be mistakenly diagnosed with hereditary FSGS leading to unnecessary further investigations, erroneous family counselling and improper corticosteroid treatment. TBMN is a frequent finding in the general population, and according to several recent reports, it may be the underlying cause and the explanation for many familial and sporadic cases of late-onset FSGS with non-nephrotic proteinuria. This is an important new finding that needs widespread recognition. It is anticipated that the molecular genetic analysis with next generation sequencing will certainly offer timely correct diagnosis.

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Co-Inheritance of Functional Podocin Variants with Heterozygous Collagen IV Mutations Predisposes to Renal Failure

Cited by 24 publications

References 39 publications

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

Digenic inheritance and genetic modifiers

Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life

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