Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome
- 699 Downloads
Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease.
Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort.
Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing.
Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.
KeywordsFamilial nephrotic syndrome Genetics EMP2 Immunity Steroid sensitivity Steroid resistance Podocyte HLA-DQA1
Epithelial member protein 2
Focal and segmental glomerulosclerosis
Steroid-resistant nephrotic syndrome
Steroid-sensitive nephrotic syndrome
Whole exome sequencing
We thank all patients with familial SSNS and their families for their participation in this study. We thank Dr Kalmàn Tory for helpful discussions.
The URLs for data presented herein are as follows:
1000genomes project: http://www.internationalgenome.org
Mutation Taster http://www.mutationtaster.org
Financial support for this work was provided by grants from the European Union’s Seventh Framework Programme (FP7/2007–2013/n°305608-EURenOmics), the “Investments for the Future” program (ANR-10-IAHU-01), and the “Fondation-maladies rares” (FONDATION_HTS-RD – I201309001) to C. Antignac, and The «Fondation pour la Recherche Médicale» (FRM n° DEA20130727711) to G. Dorval.
Compliance with ethical standards
The authors have no financial relationships relevant to this article to disclose.
Written informed consent was obtained from participants or their parents, and the study was approved by the Comité de Protection des Personnes “Ile-De-France II.”
Conflicts of interest
The authors have no conflicts of interest relevant to this article to disclose.
- 2.Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula MK, Dudley JA, Inward CD, Coward RJ, Tizard J, Reid C, Antignac C, Boyer O, Saleem MA (2014) Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol 25(6):1342–1348CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y, Hurault de Ligny B, Niaudet P, Charpentier B, Soulillou JP (1994) Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 330(1):7–14CrossRefPubMedGoogle Scholar
- 7.Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F (1996) Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334(14):878–883CrossRefPubMedGoogle Scholar
- 15.Caridi G, Gigante M, Ravani P, Trivelli A, Barbano G, Scolari F, Dagnino M, Murer L, Murtas C, Edefonti A, Allegri L, Amore A, Coppo R, Emma F, De Palo T, Penza R, Gesualdo L, Ghiggeri GM (2009) Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations. Clin J Am Soc Nephrol 4(6):1065–1072CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Ruf RG, Schultheiss M, Lichtenberger A, Karle SM, Zalewski I, Mucha B, Everding AS, Neuhaus T, Patzer L, Plank C, Haas JP, Ozaltin F, Imm A, Fuchshuber A, Bakkaloglu A, Hildebrandt F, Group APNS (2004) Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int 66(2):564–570CrossRefPubMedGoogle Scholar
- 19.Gee HY, Ashraf S, Wan X, Vega-Warner V, Esteve-Rudd J, Lovric S, Fang H, Hurd TW, Sadowski CE, Allen SJ, Otto EA, Korkmaz E, Washburn J, Levy S, Williams DS, Bakkaloglu SA, Zolotnitskaya A, Ozaltin F, Zhou W, Hildebrandt F (2014) Mutations in EMP2 cause childhood-onset nephrotic syndrome. Am J Hum Genet 94(6):884–890CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Gbadegesin RA, Adeyemo A, Webb NJ, Greenbaum LA, Abeyagunawardena A, Thalgahagoda S, Kale A, Gipson D, Srivastava T, Lin JJ, Chand D, Hunley TE, Brophy PD, Bagga A, Sinha A, Rheault MN, Ghali J, Nicholls K, Abraham E, Janjua HS, Omoloja A, Barletta GM, Cai Y, Milford DD, O'Brien C, Awan A, Belostotsky V, Smoyer WE, Homstad A, Hall G, Wu G, Nagaraj S, Wigfall D, Foreman J, Winn MP, Mid-West Pediatric Nephrology C (2015) HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. J Am Soc Nephrol 26(7):1701–1710CrossRefPubMedGoogle Scholar
- 27.Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Boyer O, Lipska-Zietkiewicz B, Gribouval O, Nitschke P, Bole C, Rothier A, Schaefer F, Antignac C (2014) Rationalizing the genetic diagnosis of SRNS/FSGS using next generation sequencing kits. J Am Soc Nephrol 25:172AGoogle Scholar
- 46.Takemoto M, He L, Norlin J, Patrakka J, Xiao Z, Petrova T, Bondjers C, Asp J, Wallgard E, Sun Y, Samuelsson T, Mostad P, Lundin S, Miura N, Sado Y, Alitalo K, Quaggin SE, Tryggvason K, Betsholtz C (2006) Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J 25(5):1160–1174CrossRefPubMedPubMedCentralGoogle Scholar
- 48.International Study of Kidney Disease in Children.(1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98(4):561–564CrossRefGoogle Scholar