Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome).
BACKGROUND
Fechtner syndrome (FTNS), also known as Alport-like syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Döhle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown.


METHODS
We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution.


RESULTS
All affected subjects presented with macrothrombocytopenia and leukocyte Döhle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9. Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic syndrome, suggesting a relationship between podocin features and proteinuria.


CONCLUSIONS
Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting.
Ghiggeri
Gian Marco
GM
Laboratory on Pathophysiology of Uremia and Laboratory of Molecular Genetics, Istituto di Ricerca e Cura a Carattere Scientifico G. Gaslini, Genova, Italy. labnefro@ospedale-gaslini.ge.it
Caridi
Gianluca
G
Magrini
Umberto
U
Sessa
Adalberto
A
Savoia
Anna
A
Seri
Marco
M
Pecci
Alessandro
A
Romagnoli
Roberta
R
Gangarossa
Simone
S
Noris
Patrizia
P
Sartore
Saverio
S
Necchi
Vittorio
V
Ravazzolo
Roberto
R
Balduini
Carlo L
CL
D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000737:chemistry; D002648:Child; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D007962:Leukocytes / Q000737:chemistry / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D020409:Molecular Motor Proteins; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000473:pathology*; D024507:Nonmuscle Myosin Type IIA / Q000096:biosynthesis / Q000235:genetics*; D013577:Syndrome
D047908:Intracellular Signaling Peptides and Proteins; C103814:MYH9 protein, human; D008565:Membrane Proteins; D020409:Molecular Motor Proteins; C407223:NPHS2 protein; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains