Rare Functional Variants of Podocin (NPHS2) Promoter in Patients With Nephrotic Syndrome

Authors: OLEGGINI, ROBERTA¹; BERTELLI, ROBERTA¹; DONATO, ARMANDO DI²; DUCA, MARCO DI²; CARIDI, GIANLUCA²; SANNA, SIMONE-CHERCHI³; SCOLARI, FRANCESCO⁴; MURER, LUISA⁵; ALLEGRI, LANDINO³; COPPO, ROSANNA⁶; EMMA, FRANCESCO⁷; CAMUSSI, GIOVANNI⁸; PERFUMO, FRANCESCO⁹; GHIGGERI, GIAN MARCO²

Source: Gene Expression, Volume 13, Number 1, 2006 , pp. 59-66(8)

Publisher: Cognizant Communication Corporation

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Abstract:

Podocin (NPHS2) is a component of the glomerular slit-diaphragm, with major regulatory functions in renal permeability of proteins. Loss of podocin and decrease in resynthesis may influence the outcome of proteinuric renal disease such as segmental glomerulosclerosis (FSGS), and promoter functionality plays a key role in this process. NPHS2 promoter variants with functional activity may be a part of the problem of podocin resynthesis. We sequenced NPHS2 promoter region from −628 to ATG in a large cohort of 260 nephrotic patients (161 with FSGS) who were presenting proteinuria from moderate to severe and were receiving or had received modular therapies according to their sensitivity to steroids and other immune modulators. Three sequence variants (−236C>T, −52C>G, −26C>G) were identified in our study population that gave an allele frequency below 1% (5 patients out of 520 alleles). Functional implications were shown for each variants that were most evident for −52C>G and −26C>G (−50% of luciferase expression compared to the wild-type sequence, p < 0.01). Consensus analysis for homology of the −52 region with regulatory factors revealed homology for USF1 and the sum of experiments with gel retardation and with cells silenced for USF1 confirmed that this factor regulates NPHS2 expression at this site. In conclusion, three functional variants in NPHS2 promoter have been identified in a large cohort of patients with nephrotic syndrome and FSGS that have a frequency <1%. One of these (i.e., −52C>G) is associated with a poor clinical outcome and evolution to end-stage renal failure. USF1 was identified as the transcriptional factor regulating NPHS2 at this site. Even if not sufficient to cause FSGS per se, these variants could represent modifiers for severity and/or progression of the disease.

Keywords: NPHS2 gene; NPHS2 promoter; Nephrotic syndrome; Focal segmental glomerulosclerosis; Proteinuria; Podocin; USF1

Document Type: Review article

Affiliations: 1: Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy, 2: Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy 3: Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Italy 4: Unit of Nephrology, Spedali Civili di Brescia, Italy 5: Department of Pediatrics, University of Padua, Italy 6: Nephrology Section, Ospedale Regina Margherita, Turin, Italy 7: Nephrology Section, Ospedale Bambin Gesù, Rome, Italy 8: Chair of Nephrology, University of Turin, Italy 9: Section of Nephrology, Istituto G. Gaslini, Genoa, Italy

Publication date: 2006-01-01

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The Molecular and Cellular Biology area of Gene Expression covers all aspects of the gene including it structure, functions, and regulation in prokaryotes, eukaryotes, and viruses; molecular and cell biological aspects of cell growth and development, chromatin structure and function. These include topics such as DNA replication, DNA repair, gene transcription, transcriptional control, RNA processing, posttranscriptional control, oncogenes, molecular mechanisms of action of hormones, molecular mechanism of cellular differentiation, growth and development, protein synthesis, and posttranslational control.
The Molecular and Cellular Neuroscience area of Gene Expression covers all aspects of gene expression as described but is devoted exclusively to the nervous system in health and disease. Topics include studies of neurogenesis, development, aging, and neurodegeneration. Complex neural systems, motor control, special senses, and higher cortical function, when viewed from the perspective of gene expression, are appropriate for the journal. Research related to molecular mechanisms of drug tolerance, dependence, and withdrawal are solicited. Manuscripts on state-of-the-art methods and protocols for molecular profiling of neuronal structure and function are welcome.

Rare Functional Variants of Podocin (NPHS2) Promoter in Patients With Nephrotic Syndrome

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