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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 Clinical history 1999 2000 2001 2002 10 year old boy 2003 2004 scarlet fever 2005 hematuria, proteinuria (7g/l), low albumin 2006 2007 2008 2009 2010 2011 2012 1. renal biopsy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 20 glomeruli slight tubular atrophy interstitial foam cells 1. renal biopsy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 slight mesangial changes 1. biopsy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 focal and segmental glomerulosclerosis global glomerulosclerosis 1. renal biopsy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 negative immunohistochemistry 1. renal biopsy 1999 2000 2001 EM from paraffin embedded material 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Alport syndrome? 2. renal biopsy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2. renal biopsy 1999 2000 thickening 2001 2002 lamellation 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 electron dense granules 2. renal biopsy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 irregular outer contour Compatible with Alport syndrome 1999 2000 2001 However: 2002 2003 hematuria was not prominent 2004 no family history of renal disease 2005 2006 2007 2008 2009 2010 2011 2012 no deafness no eye abnormalities COL4A5: no sequence abnormalities Is this really Alport? 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 recessive disease? → homozygosity mapping Regions of homozygosity 1999 2 large regions with homozygosity: 2000 2001 chromosome 8: chromosome 15: 8p23.2 – 8p23.1-p22 15q21.2 – 15q23 3535658 – 6986630 47972059 – 68741722 2002 2003 2004 2005 2006 2007 2008 2009 no genes coding collagen no genes associated with glomerular disease? 2010 2011 2012 And now? 8.6 cM 26.3 cM MYO1E 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Regions of homozygosity 1999 chromosome 15: 15q21.2 – 15q23 47972059 – 68741722 2000 2001 2002 2003 2004 2005 2006 2007 2008 MYO1E present in the candidate region on chromosome 15! large deletion: exon 19, c.1905_2049del145 2009 2010 2011 2012 MYO1E associated focal and segmental glomerulosclerosis 26.3 cM Diseases with basement membrane thickening and lamellation IgA nephropathy postinfectious GN repair resorption of immune complexes membranous GN pediatric transplants into adults Coll. α-5(IV) COL4A5 Alport syndrome Laminin LAMB2 Pierson syndrome Wilms tumor protein WT1 Frasier syndrome Paired box PAX2 protein Pax-2 renal coloboma syndrome Myosin-Ie MYO1E ass. FSGS MYO1E Melanosis of Ito Galloway-Movat syndrome immaturity hyperperfusion hyperfiltration disorganisation BM proteins dysfunction podocyte proteins not clear yet syndromes 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 Hvilke mekanismer står bak strukturforandringene ved proteinuri? GLEPP1 Actinin Phospholipase C Formin INF2 Myosin MYH9 Nephrin 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. TRPC6 WT1
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