A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population

Voskarides, Konstantinos; Stefanou, Charalambos; Pieri, Myrtani; Demosthenous, Panayiota; Felekkis, Kyriacos; Arsali, Maria; Athanasiou, Yiannis; Xydakis, Dimitris; Stylianou, Kostas; Daphnis, Eugenios; Goulielmos, GN; Loizou, Petros; Savige, Judith; Höhne, Martin; Völker, Linus A.; Benzing, Thomas; Maxwell, Patrick H.; Gale, Daniel P.; Kronenberg, Florian; Böger, Carsten A.; Kollerits, Barbara; Paulweber, Bernhard; Zavros, Michalis; Pierides, Alkis; Deltas, Constantinos

doi:10.1371/journal.pone.0174274

Cited by 21 publications

(24 citation statements)

References 63 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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“…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 . Patients carrying heterozygous COL4A mutations and co‐inheriting the variant NEPH3 ‐p.Val353Met had an increased risk to progressive kidney failure.…”

Section: Primary Mutations and Genetic Modifiers As Examples Of Pseudmentioning

confidence: 94%

“…Importantly, genetic epidemiology studies combining the general population cohorts of Framingham, KORAF4 and SAPHIR studies (11 258 individuals), revealed significant association with microalbuminuria in homozygous subjects 19 (Figure 2).…”

Section: Primary Mutations and Genetic Modifiers As Examples Of Psementioning

confidence: 98%

“…Further work with undifferentiated podocytes showed disturbance of variant p.353Met homo‐dimerization and hetero‐dimerization with nephrin, while p.353Met elicited the activation of the unfolded protein response pathway when overexpressed in stressed cultured cells, thus attesting to its functional significance. Importantly, genetic epidemiology studies combining the general population cohorts of Framingham, KORAF4 and SAPHIR studies (11 258 individuals), revealed significant association with micro‐albuminuria in homozygous subjects (Figure ).…”

Section: Primary Mutations and Genetic Modifiers As Examples Of Pseudmentioning

confidence: 99%

“…18 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. 19 Patients carrying heterozygous COL4A mutations and co-inheriting the variant NEPH3-p.Val353Met had an increased risk to progressive kidney failure. Further work with undifferentiated podocytes showed disturbance of variant p.353Met homo-dimerization and heterodimerization with nephrin, while p.353Met elicited the activation of the unfolded protein response pathway when overexpressed in stressed cultured cells, thus attesting to its functional significance.…”

Section: Primary Mutations and Genetic Modifiers As Examples Of Psementioning

confidence: 99%

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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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Expert consensus guidelines for the genetic diagnosis of Alport syndrome

et al. 2018

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Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.

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A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population

Cited by 21 publications

References 63 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

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

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