Genetics, clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA (Fechtner syndrome)

Gian Marco Ghiggeri, Gianluca Caridi, Umberto Magrini, Adalberto Sessa, Anna Savoia, Marco Seri, Alessandro Pecci, Roberta Romagnoli, Simone Gangarossa, Patrizia Noris, Saverio Sartore, Vittorio Necchi, Roberto Ravazzolo, Carlo L. Balduini

Research output: Contribution to journalArticle

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Abstract

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)95-104
Number of pages10
JournalAmerican Journal of Kidney Diseases
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 1 2003

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Nonmuscle Myosin Type IIA
Podocytes
Leukocytes
Mutation
Proteinuria
Kidney
Deafness
Cataract
Renal Insufficiency
Blood Platelets
Epithelium
Hereditary Nephritis
Nephritis
Nephrotic Syndrome
Missense Mutation
Diaphragm
Haplotypes
Electron Microscopy
Immunohistochemistry
Alleles

Keywords

  • Alport-like syndrome
  • Fechtner syndrome (FTNS)
  • Inherited glomerulonephrites
  • Nonmuscle myosin
  • Podocin

ASJC Scopus subject areas

  • Nephrology

Cite this

Genetics, clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA (Fechtner syndrome). / Ghiggeri, Gian Marco; Caridi, Gianluca; Magrini, Umberto; Sessa, Adalberto; Savoia, Anna; Seri, Marco; Pecci, Alessandro; Romagnoli, Roberta; Gangarossa, Simone; Noris, Patrizia; Sartore, Saverio; Necchi, Vittorio; Ravazzolo, Roberto; Balduini, Carlo L.

In: American Journal of Kidney Diseases, Vol. 41, No. 1, 01.01.2003, p. 95-104.

Research output: Contribution to journalArticle

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AU - Ghiggeri, Gian Marco

AU - Caridi, Gianluca

AU - Magrini, Umberto

AU - Sessa, Adalberto

AU - Savoia, Anna

AU - Seri, Marco

AU - Pecci, Alessandro

AU - Romagnoli, Roberta

AU - Gangarossa, Simone

AU - Noris, Patrizia

AU - Sartore, Saverio

AU - Necchi, Vittorio

AU - Ravazzolo, Roberto

AU - Balduini, Carlo L.

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N2 - 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. Conclusion: 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.

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