Steroid resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) are a leading cause of end-stage renal disease (ESRD) in children, adolescents and adults. Recent progress in genetics allowed for the identification of causative genes in monogenic forms of SRNS. Although several SRNS genes could be identified mostly in younger children, the genetic basis of SRNS/FSGS in adolescents and adults is far from being understood. Especially adult patients have been undersupplied with genetic testing and only fragmented data on their genotypes are available. Reliable discrimination of genetic versus non-genetic forms is an imperative as the identification of monogenic FSGS has numerous implications in a precision medicine setting. Currently, the predominant application of short-read based sequencing techniques results in preferential detection of point mutations and small sized deletions/insertions while larger structural aberrations, gene rearrangements, and mutations in genomic repeats frequently escape detection. This project combines short-read based high capacity next generation sequencing (GPS/WES/WGS) with unparalleled structural variant analyses to overcome previous limitations in genetic analyses. The major goal of this project is to unravel the genetic basis of SRNS/FSGS and to define a pipeline for the molecular genetic analyses of SRNS/FSGS as a best-practice clinical routine at UoC.
Project related publications
Siede D, Rapti K, Gorska AA, Katus HA, Altmüller J, Boeckel JN, Meder B, Maack C, Völkers M, Müller OJ, Backs J, Dieterich C. Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease. J Mol Cell Cardiol 2017 Jul 1.
Altmüller J, Haenisch B, Kawalia A, Menzen M, Nöthen MM5, Fier H and Molderings GJ. Mutational profiling in the peripheral blood leukocytes of patients with systemic mast cell activation syndrome using next-generation sequencing. Immunogenetics 2017 69:359-369
Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaite, Wessel SR, Zlatanou A, Vernet A, von Kriegsheim A, Mottram RM, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, Almoisheer A, Alsaif HS, Amar A, Prescott NJ, Bober MB, Duker A, Faqeih E, Seidahmed MZ, Al Tala S, Alswaid A, Ahmed S, Al-Aama JY, Altmüller J, Al Balwi M, Brady AF, Chessa L, Cox H, Fischetto R, Heller R, Henderson BD, Hobson E, Nürnberg P, Percin EF, Peron A, Spaccini L, Quigley AJ, Thakur S, Wise CA, Yoon G, Alnemer M, Tomancak P, Yigit G, Taylor AM, Reijns MA, Simpson MA, Cortez D, Alkuraya FS, Mathew CG, Jackson AP, Stewart GS. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat Genet. 2017 Apr;49(4):537-549.
Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, Yoshiura KI, Oufadem M, Beck TJ, McGowan R, Magee AC, Altmüller J, Dion C, Thiele H, Gurzau AD, Nürnberg P, Meschede D, Mühlbauer W, Okamoto N, Varghese V, Irving R, Sigaudy S, Williams D, Ahmed SF, Bonnard C, Kong MK, Ratbi I, Fejjal N, Fikri M, Elalaoui SC,Reigstad H, Bole-Feysot C, Nitschke P, Ragge N, Lévy N, Tuncbilek G, Teo AS, Cunningham ML, Sefiani A, Kayserili H, Murphy JM, Chatdokmaiprai C, Hillmer AM, Wattanasirichaigoon D, Lyonnet S, Magdinier F, Javed A, Blewitt ME, Amiel J,Wollnik B, Reversade B. De novo mutations in SMCHD1 cause Bosma arhiniamicrophthalmia syndrome and abrogate nasal development. Nat Genet. 2017 Feb;49(2):249-255.
Altmüller J, Motameny S, Becker C, Thiele H, Chatterjee S, Wollnik B, Nürnberg P. A systematic comparison of two new releases of exome sequencing products: the aim of use determines the choice of product. Biol Chem (2016) Aug 1; 397(8):791-801.
Büscher AK, Beck BB, Melk A, Hoefele J, Kranz B, Bamborschke D, Baig S, Lange-Sperandio B, Jungraithmayr T, Weber LT, Kemper MJ, Tönshoff B, Hoyer PF, Konrad M, Weber S; German Pediatric Nephrology Association (GPN). (2016) Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol. 2016 11, 245-53.
Laghmani K*, Beck BB*, Yang SS, Seaayfan E, Wenzel A, Reusch B, Vitzthum H, Priem D, Demaretz S, Bergmann K, Duin LK, Göbel H, Mache C, Thiele H, Bartram MP, Dombret C, Altmüller J, Nürnberg P, Benzing T, Levtchenko E, Seyberth HW, Klaus G, Yigit G, Lin SH, Timmer A, de Koning TJ, Scherjon SA, Schlingmann KP, Bertrand MJ, Rinschen MM, de Backer O, Konrad M, Kömhoff M. Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. N Engl J Med. (2016) May 12; 374(19):1853-63. *shared 1st authorship
Bartram MP, Habbig S, Pahmeyer C, Höhne M, Weber LT, Thiele H, Altmüller J, Kottoor N, Wenzel A, Krueger M, Schermer B, Benzing T, Rinschen MM*, Beck BB*. Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. Hum Mol Genet. 2016 Mar 15;25(6):1152-64.
Beck BB, Baasner A, Büscher A, Habbig S, Reintjes N, Kemper MJ, Sikora P, Mache C, Pohl M, Sathl M. Toenshoff B, Pape L, Fehrenbach H, Jacob DE, Grohe B, Wolf Mt, Nürnberg G, Yigit G, Salido EC, Hoppe (2013). Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 21,162-72.
Gee HY, Saisawat P, Ashraf S, Hurd TW, Vega-Warner V, Fang H, Beck BB, Gribouval O, Zhou W, Diaz KA, Natarajan S, Wiggins RC, Lovric S, Chernin G, Schoeb DS, Ovunc B, Frishberg Y, Soliman NA, Fathy HM, Goebel H, Hoefele J, Weber LT, Innis JW, Faul C, Han Z, Washburn J, Antignac C, Levy S, Otto EA, Hildebrandt F. ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J Clin Invest. 2013 Aug 1;123(8):3243-53.
