sabine leh
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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
10 year old boy
hematuria, proteinuria (7g/l), low albumin
scarlet fever
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1. renal biopsy
20 glomerulislight tubular atrophyinterstitial foam cells
1. renal biopsy
slight mesangial changes
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1. biopsy
global glomerulosclerosisfocal and segmental glomerulosclerosis
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1. renal biopsy
negative immunohisto-chemistry
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1. renal biopsy
EM from paraffin embedded material
Alport syndrome?
2. renal biopsy1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
2. renal biopsy1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
thickening
lamellation
electron dense granules
2. renal biopsy
irregular outer contour
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
Compatible with Alport syndrome
no family history of renal disease
COL4A5:
no deafness
no eye abnormalities
However:
Is this really Alport?
no sequence abnormalities
hematuria was not prominent
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
recessive disease? → homozygosity mapping
Regions of homozygosity
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
2 large regions with homozygosity:
chromosome 8: 8p23.2 – 8p23.1-p22 3535658 – 6986630 8.6 cMchromosome 15: 15q21.2 – 15q23 47972059 – 68741722 26.3 cM
no genes coding collagen
no genes associated with glomerular disease?
And now?
MYO1E
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
Regions of homozygosity
1999
2011
2008
2012
2000
2001
2002
2003
2004
2005
2006
2007
2009
2010
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
Diseases with basement membrane thickening and lamellation
Alport syndrome
Galloway-Movat syndrome
Frasier syndrome
Pierson syndrome
MYO1E ass. FSGS
renal coloboma syndrome
Melanosis of Ito
pediatric transplants into adults
postinfectious GN
membranous GN
IgA nephropathy repairresorption of
immune complexes
immaturityhyperperfusionhyperfiltration
disorganisationBM proteins
dysfunctionpodocyte proteins
not clear yetsyndromes
COL4A5
WT1
PAX2
LAMB2
MYO1E
Coll. α-5(IV)
Laminin
Wilms tumor protein
Paired box protein Pax-2
Myosin-Ie
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?
Pavenstädt 2003; Tryggvason 2006; Jefferson 2007;Michaud 2007; D’Agati 2011;
Nephrin
Podocin
CD2AP
TRPC6
GLEPP1
Laminin-β2
β4-integrin
Tetraspandin
Formin INF2
ActininPhospholipase C
Myosin MYH9
Myosin MYO1EWT1
Strukturelle og molekulære mekanismer ved proteinuri, 2012.