A case of glomerular basement membrane lamellation associated with mutation in the MYO1E gene and not with Alport syndrome

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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
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Clinical history
10 year old boy
scarlet fever
hematuria, proteinuria (7g/l), low albumin
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1. renal biopsy
20 glomeruli slight tubular atrophy interstitial
foam cells
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1. renal biopsy
slight mesangial changes
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1. biopsy
global glomerulosclerosis
focal and segmental glomerulosclerosis
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1. renal biopsy
negative immunohisto- chemistry
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1. renal biopsy
EM from paraffin embedded material
Alport syndrome?
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2. renal biopsy
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2. renal biopsy
thickening lamellation electron dense granules
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2. renal biopsy
irregular outer contour
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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
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recessive disease? ? homozygosity mapping
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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?
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MYO1E
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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
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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
COL4A5
Coll. a-5(IV)
disorganisation BM proteins
Pierson syndrome
LAMB2
Laminin
WT1
Wilms tumor protein
Frasier syndrome
dysfunction podocyte proteins
PAX2
Paired box protein Pax-2
renal coloboma syndrome
MYO1E ass. FSGS
MYO1E
Myosin-Ie
not clear yet syndromes
Melanosis of Ito
Galloway-Movat syndrome
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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

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Hvilke mekanismer står bak strukturforandringene
ved proteinuri?
TRPC6
GLEPP1
Actinin
Phospholipase C
Formin INF2
Myosin MYH9
Nephrin
WT1
Myosin MYO1E
Podocin
CD2AP
ß4-integrin
Laminin-ß2
Tetraspandin
Pavenstädt 2003 Tryggvason 2006 Jefferson
2007Michaud 2007 DAgati 2011
Strukturelle og molekulære mekanismer ved
proteinuri, 2012.