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M. Ludwig Group

Group leader

Apl-Prof. Dr. rer. nat. Michael Ludwig

Apl-Prof. Dr. rer. nat. Michael Ludwig


Tel.: +49 228 6885-418
Fax: +49 228 6885-401

South Zone, Building No. 76 (Life&Brain GmbH)
3rd floor

Research topics

One current research interest in our lab is describing human tubulopathies (or diseases affecting the renal tubules). In addition to Pseudohypoaldosteronism, Gitelman’s, Liddle’s, and Bartter’s syndromes, diseases such as Lowe’s syndrome, Dent disease 1, and Dent disease 2 are primary focuses of tubulopathy research. Dent’s disease is a rare, X-linked, proximal tubulopathy, which is characterized by low-molecular-weight proteinuria, nephrocalcinosis/nephrolithiasis (kidney stones), and acute kidney failure. Additional symptoms include hypercalciuria, glycosuria, aminoaciduria, and phosphaturia.[1] In the majority (ca. 55%) of Dent disease 1 patients, a defect in the CLCN5 gene is responsible for the phenotype, which codes for a voltage-gated chloride channel and Cl-/H+antiporter (ClC-5). ClC-5 is primarily expressed in the proximal tubules and α-intercalated cells of the distal tubules of the nephron and can be found in the intracellular, subapical endosomes of the epithelial cells, where it is involved with acidification and directed-transport. To date, we have been able to elucidate the CLCN5-specific phenotype of over 50 Dent’s patients through a world-wide cooperation. While searching for additional genetic causes for the disease, we were able to identify two extra CLCN5-mRNAs that are formed using four alternative exons; these mRNAs are not as widely expressed and they only differ from the normal protein in the 70 N-terminal amino acids.[2] So far, patients with a Dent-like phenotype have not been identified with mutations in these exons. Through the examination of further gene candidates, we were able to determine that another X-linked gene, CLCN4,[3] a homolog of CLCN5, as well as the (Na+K+)/H+ antiporter 7 (NHE7) are not (frequently) involved in the etiology of Dent’s disease.

Together with colleagues from Marburg, we tested nine different mutant channel proteins for their function in Xenopus laevis oocytes.[4] Nearly all of the recombinant ClC-5 mutants (truncated or with amino-acid substitution) showed a complete loss of function and no longer reached the cell membrane. In contrast, one variant (R648X) not only retained some residual activity but also showed significantly higher expression on the cell surface; an absence of the internalization motif (P670Y361 motif) likely reduces ubiquitinylation of the protein and therefore, lengthens the half-life of the protein on the surface.

Studies from our American colleagues, together with our own findings, found that mutations in the X-chromosome-localized OCRL gene can also lead to a Dent phenotype (Dent disease 2).[5,6] OCRL encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase, and defects in this gene lead, in most cases, to Lowe’s syndrome. This more serious form of Fanconi syndrome is associated with cognitive impairment, behavioral abnormalities, and cataracts. OCRL mutations were also found in 23% of our patients with the Dent phenotype.[7] Hypercalciuria has long been seen as the cardinal sign of Dent’s disease, however, our analysis has shown that rather than >95%, only 2/3 of Dent’s patients exhibit this phenotype.[8] This observation is likely to lead to an increasing number of cases being classified as Dent’s disease. Studies are still ongoing to determine whether serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels are useful parameters for differentiating between the different forms of Dent’s disease.

References

[1] Ludwig M, Utsch B, Monnens L (2006) Nephrol Dial Transplant 21: 2708-17
[2] Ludwig M, Waldegger S, Nuutinen M, Bökenkamp A, Reissinger A, Steckelbroeck S, Utsch B (2003) Kidney Blood Press Res 26: 176-84
[3] Ludwig M, Utsch B (2004) Am J Med Genet A 128A: 434-5
[4] Ludwig M, Doroszewicz J, Seyberth HW, Bökenkamp A, Balluch B, Nuutinen M, Utsch B, Waldegger S (2005) Hum Genet 117: 228-37
[5] Hoopes et al. (2005) Am J Hum Genet 76: 260-7
[6]Bökenhauer, D., Böckenkamp, A., Nuutinen, M., Unwin, R., van’t Hoff, W., Sirimanna, T., Vrljicak, K., Ludwig, M. (2012) J Pediatr Genet 1: 15-23
[7] Utsch B, Bökenkamp A, Benz MR, Besbas N, Dötsch J, Franke I, Fründ S, Gok F, Hoppe B, Karle S, Kuwertz-Bröking E, Laube G, Neb M, Nuutinen M, Ozaltin F, Rascher W,  Ring T, Tasic V, van Wijk JAE, Ludwig M (2006) Am J Kidney Dis 48: 942-54
[8] Ludwig M, Utsch B, Balluch B, Fründ S, Kuwertz-Bröking E, Bökenkamp A (2006) Pediatr Nephrol 21: 1241-50

A second area of research currently in our lab is the determination of the etiology of bladder exstrophy-epispadias complex (BEEC). BEEC represents one of the most severe congenital urogenital deformities, which describes a spectrum of abnormalities from epispadias and exstrophy of the urinary bladder to the most severe form, exstrophy of the cloaca, and is found in approximately 1:10,000 European births.[1, 2] Epidemiological information from our own study of 151 patients, as well as a broader study, have pointed to a multi-factorial origin of the defect.[3] This leads to a 400 times increased risk of recurrence in siblings of an affected individual,[4] when compared to the general population, and also our group’s comparative analysis of monozygotic and dizygotic twins points to a significant genetic component to the etiology of BEEC.[2]A variety of preliminary studies have identified possible gene candidates for their influence on the development of BEEC through sequencing data,[5,6] in particular by using association studies and genome-wide matrix-CGH arrays.[7,8] Further analysis using gene candidates derived from murine knock-out models, such as the knock-out model, ΔNp63,[9] for an isoform of the p63 gene,are currently being evaluated. Together with Prof. Boyadjiev (Section of Genetics, Department of Pediatrics, University of California Davis), analysis of genomic DNA/RNA taken from exstrophic bladder tissue has begun with respect to ΔNp63. In collaboration with the Max-Delbrück Center in Berlin, we have undergone a genome-wide association analysis on three multiplex families.[10] With the help of this study, we hope to identify for the first time, regions of the human genome with a higher probability to contain genes related to the formation of BEEC. We have now begun to map the genes in this region by systematically sequencing affected family members.

In one of the first genome-wide association studies, and with the help of expression data from the mouse, we have identified a highly conserved 32 kb region that lies between the WNT3 and WNT9b genes as a possible susceptibility locus for the isolated form of classical bladder exstrophy.[11]Through further analysis in zebrafish, we were able to confirm the involvement of the WNT3 gene.[12] With the help of continued genome-wide association studies and a meta-analysis of a large patient collective, we were able to associate an additional gene with BEEC, namely ISL1.[13,14]

References

[1] Ludwig M, Utsch B, Reutter H (2005) Urologe A 44:1037-1044
[2] Reutter H, Qi L, Gearhart JP, Boemers T, Ebert AK, Rösch W, Ludwig M, Boyadjev, SA (2007) Am J Med Genet A 143A: 2751-2756
[3] Boyadjiev et al. (2004) BJU Int 94:1337-1343
[4] Shapiro et al. (1984) J Urol 132:308-310
[5] Reutter H, Thauvin-Robinet C, Boemers TM, Rösch W, Ludwig M (2006) Scand J Urol Nephrol 40:221-224
[6] Krüger V, Khoshvaghti M, Reutter H, Vogt H, Boemers TM, Ludwig M (2008) Pediatr Surg Int 24: 893-897
[7] Reutter H, Becker T, Ludwig M, Schäfer N, Detlefsen B, Beaudoin S, Fisch M, Ebert AK, Rösch W, Nöthen MM, Boemers TM, Betz RC (2006) Am J Med Genet A 140A:2506-2509
[8] Reutter H,  Hoischen A, Ludwig M, Stein R, Radlwimmer B, Engels H, Wolffenbuttel K, Weber RG (2007) BJU Int 100:646-650
[9] Cheng et al. (2006) Development 133: 4783-4792
[10] Ludwig M, Rüschendorf F, Hübner N, Saar K, Siekmann L, Boyadjiev SA, Reutter H (2009) Birth Defects Res A Clin Mol Teratol 85: 174-178136.
[11] Reutter H, Draaken M, Pennimpede T, et al. (2014) Hum Mol Genet 23: 5536-5544.
[12] Baranowska Korberg I, Hofmeister W, Markljung E, et al. (2015) Hum Mol Genet  24: 5069-5078.
[13] Draaken M, Knapp M, Pennimpede T, et al. (2015) PloS Genet 2015; 11: e1005024.
[14] Zhang R, Knapp M, Suzuki K, et al. (2017) Sci Rep 2017; 7: 42170.

A further field of study within routine patient care is the characterization of various rare diseases associated with a disruption in hemoglobin biosynthesis (see HbBonn, Clin Chem 2008, 54:594-6).

 

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