Donnai–Barrow syndrome in nephrology practice

Donnai–Barrow syndrome is a multi-system disorder characterized by a variable combination of congenital anomalies, progressive myopia, sensorineural hearing loss, intellectual disability and renal disease. The article describes clinical cases of children with different phenotypes of the syndrome, including different renal disorders. One patient had isolated low-molecular-weight proteinuria, another patient suffered from proteinuria, hypercalciuria, nephrocalcinosis. Disruption of megaline-mediated endocytosis, retrograde endosomal transport of ligands, mitochondrial dysfunction, stress of the endoplasmic reticulum can lead to a different spectrum and various degrees of severity of tubular dysfunction in Donnai-Barrow syndrome. A variety of clinical manifestations of the disease can lead to a low diagnosis of Donnai-Barrow syndrome and inadequate patient management.

1. Marzolo M.P., Farfán P. New insights into the roles of megalin/LRP2 and the regulation of its functional expression. Biol Res 2011; 44(1): 189–105. DOI: 10.4067/S071697602011000100012

2. De S., Kuwahara S., Saito A. The endocytic receptor megalin and its associated proteins in proximal tubule epithelial cells. Membranes 2014; 4(3): 333–355. DOI: 10.3390/membranes4030333

3. Fisher C.E., Howie S.E.M. The role of megalin (LRP-2/Gp330) during development. Dev Biol 2006; 296(2): 279– 297. DOI: 10.1016/j.ydbio.2006.06.007

4. Christ A., Herzog K., Willnow T.E. LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease. Dev Dyn 2016; 245(5): 569–579. DOI: 10.1002/dvdy.24394

5. Baardman M.E., Zwier M.V., Wisse L.J., Gittenberger-de Groot A.C., Kerstjens-Frederikse W.S., Hofstra R.M.W. et al. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development. Disease Models & Mechanisms 2016; 9: 413–42. DOI: 10.1242/dmm.022053

6. Storm T., Heegaard S., Christensen E.I., Nielsen R. Megalin deficiency causes high myopia, retinal pigment epithelium-macromelanosomes and abnormal development of the ciliary body in mice. Cell Tissue Res 2014; 358(1): 99–107. DOI: 10.1007/s00441-014-1919-4

7. Cases O., Joseph A., Obry A., Santin M.D., Ben-Yacoub S., Pâques M. et al. Foxg1-Cre mediated Lrp2 inactivation in the developing mouse neural retina, ciliary and retinal pigment epithelia models congenital high myopia. PLoS One 2015; 10: e0129518. DOI: 10.1371/journal.pone.0129518

8. Greer J., Babiuk R., Thebaud B. Etiology of Congenital Diaphragmatic Hernia: The Retinoid Hypothesis. Pediatr Res 2003; 53(5): 726–730. DOI: 10.1203/01.PDR.0000062660.12769.E6

9. Wynn Y., Yu L., Chung W.K. Genetic causes of congenital diaphragmatic hernia. Semin Fetal Neonatal Med 2014; 19(6): 324–330. DOI: 10.1016/j.siny.2014.09.003.

10. Tedja M.S., Haarman A.E.G., Meester-Smoor M.A., Verhoeven V.J.M., Klaver C.C.W., MacGregor S. The Genetics of Myopia. In: M. Ang, T. Wong (eds). Updates on Myopia. Springer, Singapore, 2020. DOI: 10.1007/978-981-13-8491-2_5

11. Chassaing N., Lacombe D., Carles D., Calvas P., Saura R., Bieth E. Donnai-Barrow syndrome: four additional patients. Am J Med Genet A 2003; 121A(3): 258–262. DOI: 10.1002/ajmg.a.20266

12. Khalifa O., Al-Sahlawi Z., Imtiaz F., Ramzan K., Allam R., Al-Mostafa A. et al. Variable expression pattern in Donnai-Barrow syndrome: report of two novel LRP2 mutations and review of the literature. Eur J Med Genet 2015; 58(5): 293–299. DOI: 10.1016/j.ejmg.2014.12.008

13. Pober B.R., Longoni M., Noonan K.M. A review of Donnai-Barrow and facio-oculo-acoustico-renal (DB/FOAR) syndrome: clinical features and differential diagnosis. Birth Defects Res A Clin Mol Teratol 2009; 85(7): 76–81. DOI: 10.1002/bdra.20534

14. Schrauwen I., Sommen M., Claes C., Pinner J., Flaherty M., Collins F., Van Camp G. Broadening the phenotype of LRP2 mutations: A new mutation in LRP2 causes a predominantly ocular phenotype suggestive of Stickler syndrome. Clin Genet 2014; 86(3): 282–286. DOI: 10.1111/cge.12265

15. Dachy A., Paquot F., Debray G., Bovy C., Christensen E.I., Collard L., Jouret F. In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction. Pediatr Nephrol 2015; 30(3):1027–1031. DOI:10.1007/s00467014-3037-7

16. Kantarci S., Al-Gazali L., Hill R.S., Donnai D., Black G.C.M., Bieth E. et al. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet 2007; 39(8): 957– 959. DOI: 10.1038/ng2063

17. Anglani F., Terrin L., Brugnara M., Battista M., Cantaluppi V., Ceol M. et al. Hypercalciuria and nephrolithiasis: expanding the renal phenotype of Donnai-Barrow syndrome. Clin Genet 2018; 94(1): 187–188. DOI: 10.1111/cge.13242

18. Flemming J., Marczenke M., Rudolph I.M., Nielsen R., Storm T., Erik I.C. et al. Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome. Kidney Int 2020; 98(1): 159–167. DOI: 10.1016/j.kint.2020.02.021

19. Shaheen I.S., Finlay E., Prescott K., Russell M., Longoni M., Joss S. Focal segmental glomerulosclerosis in a female patient with Donnai–Barrow syndrome. Clin Dysmorphol 2010; 19(1): 35–37. DOI: 10.1097/MCD.0b013e328333c20a

20. Storm T., Tranebj rg L., Frykholm C., Birn H., Verroust P.J., Nevéus T. et al. Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration. Nephrol Dial Transplant 2013; 28(3): 585–591. DOI: 10.1093/ndt/gfs462

21. Yoshida H. ER stress and diseases. FEBS J 2007; 274(3): 630– 658. DOI: 10.1111/j.1742-4658.2007.05639.x

22. Li Q., Lei F., Tang Y., Pan J.S., Tong Q., Sun Y., Sheikh-Hamad D. Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism. Cell Mol Life Sci 2018; 75(21): 4021–4040. DOI: 10.1007/s00018018-2847-3

23. Johannes L., Popoff V. Tracing the retrograde route in protein trafficking. Cell 2008; 135(7): 1175–1187. DOI: 10.1016/j.cell.2008.12.009

24. Nielsen R., Courtoy P.J., Jacobsen C., Dom G., Lima W.R., Jadot M. et al. Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc Natl Acad Sci U S A 2007; 104(13): 5407–5412. DOI: 10.1073/pnas.0700330104

25. Anglani F., Gianesello L., Beara-Lasic L., Lieske J. Dent disease: A window into calcium and phosphate transport. J Cell Mol Med 2019; 23(11): 7132–7142. DOI: 10.1111/jcmm.14590

26. Patrie K.M., Drescher A.J., Welihinda A., Mundel P., Margolis B. Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4, with the tight junction protein MAGI-1. J Biol Chem 2002; 277(33): 30183–30190. DOI: 10.1074/jbc.M203072200

27. Stora S., Conte M., Chouery E., Richa S., Jalkh N., Gillart A.C. et al. A 56-year-old female patient with facio-oculo-acoustico-renal syndrome (FOAR) syndrome. Report on the natural history and of a novel mutation. Eur J Med Genet 2009; 52(5): 341–343. DOI: 10.1016/j.ejmg.2009.06.005