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Sabine Leh

A case of glomerular basement membrane lamellation associated with mutation in the MYO1E gene and not with Alport syndrome. Sabine Leh. Damien Brackman, Izeta Mujic, Helge Boman, Einar Svarstad, Torunn Fiskerstrand. Bergen, Norway. 1999. 2000. 2001. 2002. 2003. 2004. 2005. 2006. 2007.

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Sabine Leh

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  1. A case of glomerular basement membrane lamellation associated with mutation in the MYO1E gene and not with Alport syndrome Sabine Leh Damien Brackman, Izeta Mujic, Helge Boman, Einar Svarstad, Torunn Fiskerstrand Bergen, Norway

  2. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Clinical history 10 year old boy scarlet fever hematuria, proteinuria (7g/l), low albumin

  3. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 1. renal biopsy 20 glomeruli slight tubular atrophy interstitial foam cells

  4. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 1. renal biopsy slight mesangial changes

  5. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 1. biopsy focal and segmental glomerulosclerosis global glomerulosclerosis

  6. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 1. renal biopsy negative immunohisto- chemistry

  7. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 1. renal biopsy EM from paraffin embedded material Alport syndrome?

  8. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2. renal biopsy

  9. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2. renal biopsy thickening lamellation electron dense granules

  10. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2. renal biopsy irregular outer contour

  11. Compatible with Alport syndrome 1999 2000 2001 However: 2002 hematuria was not prominent 2003 2004 no family history of renal disease 2005 no deafness 2006 no eye abnormalities 2007 2008 COL4A5: no sequence abnormalities 2009 Is this really Alport? 2010 2011 2012

  12. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 recessive disease? → homozygosity mapping

  13. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Regions of homozygosity 2 large regions with homozygosity: chromosome 8: 8p23.2 – 8p23.1-p22 3535658 – 6986630 8.6 cM chromosome 15: 15q21.2 – 15q23 47972059 – 68741722 26.3 cM no genes coding collagen no genes associated with glomerular disease? And now?

  14. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 MYO1E

  15. 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Regions of homozygosity chromosome 15: 15q21.2 – 15q23 47972059 – 68741722 26.3 cM MYO1E present in the candidate region on chromosome 15! large deletion: exon 19, c.1905_2049del145 MYO1E associated focal and segmental glomerulosclerosis

  16. Diseases with basement membrane thickening and lamellation IgA nephropathy repair resorption of immune complexes postinfectious GN membranous GN immaturity hyperperfusion hyperfiltration pediatric transplants into adults Alport syndrome Coll. α-5(IV) COL4A5 disorganisation BM proteins Pierson syndrome Laminin LAMB2 Wilms tumor protein WT1 Frasier syndrome dysfunction podocyte proteins Paired box protein Pax-2 PAX2 renal coloboma syndrome MYO1E ass. FSGS Myosin-Ie MYO1E not clear yet syndromes Melanosis of Ito Galloway-Movat syndrome

  17. Summary • Basement membrane thickening and lamellation is not specific for Alport syndrome • The pathogenetic mechanism has not been resolved • Both repair, immaturity, disorganisation and podocyte dysfunction might play a role

  18. Hvilke mekanismer står bak strukturforandringene ved proteinuri? TRPC6 GLEPP1 Actinin Phospholipase C Formin INF2 Myosin MYH9 Nephrin WT1 Myosin MYO1E Podocin CD2AP β4-integrin Laminin-β2 Tetraspandin Pavenstädt 2003; Tryggvason 2006; Jefferson 2007;Michaud 2007; D’Agati 2011; Strukturelle og molekulære mekanismer ved proteinuri, 2012.

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