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• W2071289299 abstract "Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May–Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS–FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype–phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS. Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May–Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS–FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype–phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS. May–Hegglin anomaly and Sebastian syndrome are rare autosomal dominant disorders characterized by thrombocytopenia, giant platelets, and granulocyte cytoplasmic inclusion bodies called Döhle body-like inclusion bodies.1.Saito H. Kunishima S. Historical hematology: May-Hegglin anomaly.Am J Hematol. 2008; 83: 304-306Crossref PubMed Scopus (32) Google Scholar There are two related disorders, namely, Fechtner syndrome (FTNS) and Epstein syndrome (EPS), in which progressive hearing disability and nephritis are observed.1.Saito H. Kunishima S. Historical hematology: May-Hegglin anomaly.Am J Hematol. 2008; 83: 304-306Crossref PubMed Scopus (32) Google Scholar In FTNS, cataract is also present. Recently, MYH9, a gene encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), has been identified as the causative gene for these four disorders.2.Kunishima S. Kojima T. Tanaka T. et al.Mapping of a gene for May-Hegglin anomaly to chromosome 22q.Hum Genet. 1999; 105: 379-383Crossref PubMed Scopus (45) Google Scholar, 3.Seri M. Cusano R. Gangarossa S. et al.The May-Heggllin/Fechtner Syndrome Consortium. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes.Nat Genet. 2000; 26: 103-105Crossref PubMed Scopus (380) Google Scholar, 4.Kelley M.J. Jawien W. Ortel T.L. et al.Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly.Nat Genet. 2000; 26: 106-108Crossref PubMed Scopus (210) , 5.Kunishima S. Kojima T. Matsushita T. et al.Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome).Blood. 2001; 97: 1147-1149Crossref PubMed Scopus (117) Google Scholar Several mutations in MYH9 have been identified, and the existence of mutational hot spots in MYH9, that is, codons R702, R1165, D1424, E1841, and R1933, has been reported.6.Kunishima S. Matsushita T. Kojima T. et al.Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions.J Hum Genet. 2001; 46: 722-729Crossref PubMed Scopus (98) Google Scholar, 7.Heath K.E. Campos-Barros A. Toren A. et al.Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes.Am J Hum Genet. 2001; 69: 1033-1045Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar, 8.Dong F. Li S. Pujol-Moix N. et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia.Br J Haematol. 2005; 130: 620-627Crossref PubMed Scopus (80) Google Scholar, 9.Pecci A. Panza E. Pujol-Moix N. et al.Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.Hum Mutat. 2008; 29: 409-417Crossref PubMed Scopus (143) Google Scholar As mutations in a single gene cause four distinct disorders, a novel nomenclature, MYH9 disorders, has been proposed.6.Kunishima S. Matsushita T. Kojima T. et al.Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions.J Hum Genet. 2001; 46: 722-729Crossref PubMed Scopus (98) Google Scholar, 8.Dong F. Li S. Pujol-Moix N. et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia.Br J Haematol. 2005; 130: 620-627Crossref PubMed Scopus (80) Google Scholar, 10.Seri M. Pecci A. Di Bari F. et al.MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.Medicine (Baltimore). 2003; 82: 203-215Crossref PubMed Google Scholar However, the mechanisms by which mutations in a single gene cause a variety of phenotypes remain to be elucidated.1.Saito H. Kunishima S. Historical hematology: May-Hegglin anomaly.Am J Hematol. 2008; 83: 304-306Crossref PubMed Scopus (32) Google Scholar Certain mutations in MYH9 have been associated with the development of renal phenotypes, and R702 mutation is one of these.7.Heath K.E. Campos-Barros A. Toren A. et al.Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes.Am J Hum Genet. 2001; 69: 1033-1045Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar, 8.Dong F. Li S. Pujol-Moix N. et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia.Br J Haematol. 2005; 130: 620-627Crossref PubMed Scopus (80) Google Scholar, 9.Pecci A. Panza E. Pujol-Moix N. et al.Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.Hum Mutat. 2008; 29: 409-417Crossref PubMed Scopus (143) Google Scholar, 10.Seri M. Pecci A. Di Bari F. et al.MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.Medicine (Baltimore). 2003; 82: 203-215Crossref PubMed Google Scholar Nevertheless, detailed information on renal manifestations, renal histology, and prognosis has been lacking. In addition to macrothrombocytopenic diseases due to MYH9 mutations, a significant association between the development of idiopathic focal segmental glomerulosclerosis (FSGS) or end-stage renal disease (ESRD) in African-American individuals and single-nucleotide polymorphisms in MYH9 was identified in 2008.11.Kopp J.B. Smith M.W. Nelson G.W. et al.MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.Nat Genet. 2008; 40: 1175-1184Crossref PubMed Scopus (587) Google Scholar, 12.Kao W.H. Klag M.J. Meoni L.A. et al.MYH9 is associated with nondiabetic end-stage renal disease in African Americans.Nat Genet. 2008; 40: 1185-1192Crossref PubMed Scopus (536) Google Scholar This finding shows that NMMHC-IIA is responsible for not only EPS–FTNS, but also FSGS. Structural or functional abnormalities of NMMHC-IIA are considered to be critical in the development of FSGS in the African-American population. In this study, we analyzed nine cases with R702 mutation in MYH9. Most cases with R702 mutation in MYH9 develop nephritis characterized by proteinuria and/or hematuria in early infancy, and the deterioration of renal function accelerates in early adolescence. Hearing disability also manifests in early infancy and progresses to deafness at approximately 30 years of age. Findings of a serial renal biopsy in one case indicated that the pathological feature underlying this progressive nephritis is FSGS. The clinical backgrounds of each case are summarized in Table 1. The age at the latest examination ranges from 4 to 33 years. Most of the cases were diagnosed as having idiopathic thrombocytopenic purpura at first presentation.Table 1Clinical backgrounds and renal manifestations in patients with R702 mutation in MYH9Case no.SexEthnic backgroundMYH9 mutationFirst clinical diagnosisAge and urinalysis findings when urine abnormalities were first notedAge at latest evaluation and each clinical statusAgeProteinuriaHematuriaAgeClinical statusAge at CKD 5 onsetProteinuriaHematuria1FJapaneseR702HITP(−)(−)4y11mw.n.l(−)(−)2FJapaneseR702CMHA2y7m(1+)(−)4y2mCKD stage 1(−)(−)3FChineseR702CITP6y8m(−)(1+)6y8mCKD stage 1(−)(1+)4MJapaneseR702CITP5y8m(2+)(3+)12y3mCKD stage 1(3+)(3+)5MJapaneseR702CITP11y8m(+)(+/−)11y8mCKD stage 1(+)(+/−)6FJapaneseR702CITP8y8m(1+)(1+)21y3mTransplant15y7MJapaneseR702CMHA9y(1+)(1+)20y7mTransplant17y8FJapaneseR702CITPUnknownUnknown33yPD/HD16y9FJapaneseR702CITP5y8m(+/–)Unknown32yTransplant20yAbbreviations: HD, hemodialysis; HPF, high power fields; ITP, idiopathic thrombocytopenic purpura; MHA, May–Hegglin anomaly; m, month; PD, peritoneal dialysis; y, year.In the urinalysis, stages of proteinuria and hematuria were defined as follows:Proteinuria: +/-, 15 mg/dl; +, 30 mg/dl; 2+, 100 mg/dl; 3+. 300 mg/dl or over 300 mg/dl.Hematuria: +/-, RBC ∼5/HPF; 1+, 5-10/HPF; 2+, 10∼50/HPF; 3+, >50-100/HPF. Open table in a new tab Abbreviations: HD, hemodialysis; HPF, high power fields; ITP, idiopathic thrombocytopenic purpura; MHA, May–Hegglin anomaly; m, month; PD, peritoneal dialysis; y, year. In the urinalysis, stages of proteinuria and hematuria were defined as follows: Proteinuria: +/-, 15 mg/dl; +, 30 mg/dl; 2+, 100 mg/dl; 3+. 300 mg/dl or over 300 mg/dl. Hematuria: +/-, RBC ∼5/HPF; 1+, 5-10/HPF; 2+, 10∼50/HPF; 3+, >50-100/HPF. Genetic analysis revealed R702H mutation in case 1 and R702C mutation in the remaining 8 cases. All the R702 mutations identified in this study were de novo mutations. No disease-related family histories were noted. The renal manifestations of nine cases are described in Table 1. Except for case 1, all the other cases developed proteinuria and/or hematuria before 12 years of age. Case 2 developed significant proteinuria (1+; urine protein/gCr=310 mg/g creatinine (Cr)) as early as 2 years and 7 months of age. It is notable that four cases over 15 years old developed ESRD between 15 and 20 years of age. Distinct from another progressive hereditary nephritis, that is, Alport’s syndrome, none of the cases showed macroscopic hematuria at presentation. For cases 6, 7, 8, and 9 who developed ESRD, their serum Cr levels are plotted in Figure 1. Each case progressed to ESRD shortly after the serum Cr level exceeded 1.0 mg/dl. The clinical status at the latest evaluation is described in Table 1 along with age at final evaluation. Among these cases, only case 1 showed cataract (Table 2). A hearing disability was observed in most of the cases by approximately 5 years of age, which progressed rapidly. Over 30 years old, all of the cases in this study became deaf.Table 2Extrarenal manifestations in each patientCase no.Type of cytoplasmic distribution of NMMHC-IIAHearing disabilityCataractAge of presentation and severityLatest hearing level1II2y2m: 50 dbNT+2II(−)(−)(−)3II(−)(−)(−)4II4yNT(−)5II4y40–50 dB(−)6II8y10m: 30 dB40–55 dB(−)7II10y70–80 dB(−)8II9yDeaf(−)9II5yDeaf(−)Abbreviations: m, month; NMMHC-IIA, nonmuscle myosin heavy chain IIA; NT, not tested; y, year.Note: Abnormal distributions of NMMHC-IIA are classified into three types according to the number, size, and shape of accumulated NMMHC-IIA granules (see also the Materials and Methods section).16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar Type II is characterized by the presence of up to 20 circular to oval NMMHC-IIA-positive spots (≤1 μm). Open table in a new tab Abbreviations: m, month; NMMHC-IIA, nonmuscle myosin heavy chain IIA; NT, not tested; y, year. Note: Abnormal distributions of NMMHC-IIA are classified into three types according to the number, size, and shape of accumulated NMMHC-IIA granules (see also the Materials and Methods section).16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar Type II is characterized by the presence of up to 20 circular to oval NMMHC-IIA-positive spots (≤1 μm). Light and electron microscopy findings of serial renal biopsies of specimens from case 6 are shown in Figure 2. The first biopsy was performed at 9 years of age by surgical operation, when the serum Cr level was 0.4 mg/dl. Twenty-four glomeruli were obtained, and mild mesangial cell proliferations and expansion were observed in most glomeruli (Figure 2a). Sclerotic lesions were not observed in any glomeruli, and tubulointerstitial changes were minimal. Immunofluorescence studies using immunoglobulins G, A, M, and C1q, C3, and C4 antibodies showed negative or no significant findings. Electron microscopy of these specimens revealed focal lesions of podocyte foot process effacement (indicated by an arrow in Figure 2c). Focal glomerular basement membrane (GBM) thickening lesions were observed (up to 1000–1500 nm in diameter), whereas most GBM show normal appearance (thickness ranges from 300 to 400 nm). The other GBM abnormalities, such as splitting, attenuation, or reticulation, were not observed. The second biopsy was performed by needle biopsy when the case was 11 years and 9 months of age. Only four glomeruli were obtained; one glomerulus showed global sclerosis, and two of the remaining three glomeruli showed segmental sclerosis. The glomeruli were not enlarged. Interstitial fibrosis, cellular infiltration, and tubular atrophy were observed around the impaired glomeruli. At the time of the second renal biopsy, the serum Cr level was 0.6 mg/dl, and the estimated glomerular filtrate rate calculated by Schwartz's formula was 107 ml/min per 1.73 m2. The findings of the second biopsy of case 6 are compatible with the diagnosis of FSGS. Considering an almost normal glomerular filtrate rate at the time of the second renal biopsy, absence of enlarged glomeruli in the kidney specimen, and the subsequent rapid progression to ESRD in this patient, focal segmental sclerosis is considered to be the primary lesion due to MYH9 mutation rather than a phenomenon secondary to nephron mass reduction. Figure 3 shows the immunostaining data of NMMHC-IIA in the glomerulus in normal control and case 6 kidney samples. In the glomeruli of the control sample, the intensity of NMMHC-IIA immunostaining is very strong in podocytes (Figure 3a and b). In the first biopsy specimen from case 6, the intensity of immunostaining of NMMHC-IIA is already significantly decreased (Figure 3c and d). The second biopsy specimen from case 6 (Figure 3e and f) also shows a decreased NMMHC-IIA immunostaining intensity. In the normal kidney sample, NMMHC-IIA is also expressed in renal tubular cells, particularly those of the distal tubule, Henle's loop, and proximal tubular cells (Figure 4a-d). Endothelial cells of interlobular arteries and arterioles, and peritubular capillaries also express NMMHC-IIA (Figure 4a-c). In case 6, NMMHC-IIA expression in renal tubular cells and endothelial cells did not change significantly (Figure 4e and f). The NMMHC-IIA distribution pattern in peripheral blood neutrophils was examined by immunofluorescence analysis. In normal blood neutrophils, NMMHC-IIA distributes diffusely in the cytoplasm (Figure 5, control 1, 2, and 3). In all the cases with MYH9 R702 mutations, NMMHC-IIA was condensed and localized in the peripheral region of neutrophils (Figure 5, cases 1–9; condensation of NMMHC-IIA is indicated by an arrowhead). This granular pattern (type II) was observed in neutrophils from all the cases with R702 mutations (Figure 5 and Table 2, see Methods and Discussion sections for the definition of NMMHC-IIA distribution patterns in neutrophils). Three cases, namely cases 2, 4, and 7, were treated with angiotensin receptor blockers (ARB) and/or angiotensin-converting enzyme inhibitors (ACEIs) for progressive nephritis. Figure 6 shows the effect of ARB/ACEI on urinary protein level in case 2. The urinary protein level evaluated in terms of urine protein/Cr was decreased from 500–700 mg/gCr to approximately 100 mg/gCr by administration of 20 mg of valsartan (Figure 6). In cases 4 and 7, the effect of ARB/ACEI was not very conclusive (data not shown). In case 4, other drugs such as cyclosporine A were used simultaneously; therefore, the effect of only ARB/ACEI could not be determined. In case 7, the effect of ARB/ACEI was transient. In this study, we showed that cases with MYH9 R702 mutation show a very rapid deterioration of renal function with concurrent progressive hearing disability. Proteinuria and/or hematuria was detected in early infancy, and ESRD developed during adolescence. To date, several mutations including S96L, R702C, R702H, R1165C, and D1424 have been associated with the development of nephritis.7.Heath K.E. Campos-Barros A. Toren A. et al.Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes.Am J Hum Genet. 2001; 69: 1033-1045Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar, 8.Dong F. Li S. Pujol-Moix N. et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia.Br J Haematol. 2005; 130: 620-627Crossref PubMed Scopus (80) Google Scholar, 9.Pecci A. Panza E. Pujol-Moix N. et al.Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.Hum Mutat. 2008; 29: 409-417Crossref PubMed Scopus (143) Google Scholar, 10.Seri M. Pecci A. Di Bari F. et al.MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.Medicine (Baltimore). 2003; 82: 203-215Crossref PubMed Google Scholar Pecci et al.9.Pecci A. Panza E. Pujol-Moix N. et al.Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.Hum Mutat. 2008; 29: 409-417Crossref PubMed Scopus (143) Google Scholar showed that mutations in the motor domain of NMMHC-IIA are associated with severe thrombocytopenia and the development of nephritis and deafness before 40 years of age, whereas patients with mutations in the tail domain not only have a much lower risk of developing such impairments but also significantly higher platelet counts. Heath et al.7.Heath K.E. Campos-Barros A. Toren A. et al.Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes.Am J Hum Genet. 2001; 69: 1033-1045Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar and Dong et al.8.Dong F. Li S. Pujol-Moix N. et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia.Br J Haematol. 2005; 130: 620-627Crossref PubMed Scopus (80) Google Scholar described the development of nephritis in patients with R702 mutations. However, description of the clinical course of nephritis in these reports was very limited. In this study, we examined the precise clinical manifestations in nine patients with MYH9 R702 mutations, and showed a definite genotype–phenotype correlation in both renal impairment and hearing disability. In Epstein–Fechtner syndrome, renal biopsy is principally contraindicated because of the accompanying thrombocytopenia. There have been few reports on the morphological changes of renal histology in Epstein–Fechtner syndrome. Only three reports on renal pathological findings are available in the literature.13.Epstein C.J. Sahud M.A. Piel C.F. et al.Hereditary macrothrombocytopathia, nephritis and deafness.Am J Med. 1972; 52: 299-310Abstract Full Text PDF PubMed Scopus (187) Google Scholar, 14.Moxey-Mims M.M. Young G. Silverman A. et al.End-stage renal disease in two pediatric patients with Fechtner syndrome.Pediatr Nephrol. 1999; 13: 782-786Crossref PubMed Scopus (21) Google Scholar, 15.Ghiggeri G.M. Caridi G. Magrini U. et al.Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome).Am J Kidney Dis. 2003; 41: 95-104Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Epstein et al.13.Epstein C.J. Sahud M.A. Piel C.F. et al.Hereditary macrothrombocytopathia, nephritis and deafness.Am J Med. 1972; 52: 299-310Abstract Full Text PDF PubMed Scopus (187) Google Scholar described the renal morphology in a 13-year-old patient with Epstein syndrome. Their study revealed interstitial fibrosis, focal mesangial proliferation, and global sclerotic changes when the serum Cr level was 0.6 mg/dl. A recent genetic study by Heath et al.7.Heath K.E. Campos-Barros A. Toren A. et al.Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes.Am J Hum Genet. 2001; 69: 1033-1045Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar identified MYH9 R702C mutation in this patient. Moxey-Mims et al.14.Moxey-Mims M.M. Young G. Silverman A. et al.End-stage renal disease in two pediatric patients with Fechtner syndrome.Pediatr Nephrol. 1999; 13: 782-786Crossref PubMed Scopus (21) Google Scholar performed renal biopsy twice in an African-American female with Fechtner's syndrome. The type of MYH9 mutation in this patient was not identified in the literature. The first biopsy at 7 years of age showed proliferation of mesangial cells and matrix with alterations in the GBM, such as effacement, thickening, and splitting; the second biopsy at 10 years of age revealed global sclerotic changes in 75% of glomeruli.14.Moxey-Mims M.M. Young G. Silverman A. et al.End-stage renal disease in two pediatric patients with Fechtner syndrome.Pediatr Nephrol. 1999; 13: 782-786Crossref PubMed Scopus (21) Google Scholar Moxey-Mims et al.14.Moxey-Mims M.M. Young G. Silverman A. et al.End-stage renal disease in two pediatric patients with Fechtner syndrome.Pediatr Nephrol. 1999; 13: 782-786Crossref PubMed Scopus (21) Google Scholar concluded that these renal changes are similar to those in Alport syndrome. Ghiggeri et al.15.Ghiggeri G.M. Caridi G. Magrini U. et al.Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome).Am J Kidney Dis. 2003; 41: 95-104Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar performed renal biopsy in FTNS patients with D1424H mutation, and electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. The histopathological changes reported so far could occur in various types of glomerulonephritis. In this study, renal biopsy was performed twice in case 6 with platelet transfusion. The second renal biopsy specimen from case 6 showed that the pathological diagnosis is FSGS. In Epstein–Fechtner's syndrome with R702 mutation, progressive proteinuria and rapid deterioration of renal function are the common characteristics, as shown in this study, and the renal histology in case 6 is compatible with the clinical features of Epstein–Fechtner's syndrome with MYH9 R702 mutation. Epstein syndrome has been considered to be a variant of Alport syndrome, because of their very similar phenotypes, except for macrothrombocytopenic purpura, which is observed only in Epstein syndrome. However, the following two lines of evidence make them distinct from each other. The first is the different types of urinary abnormality. As shown in Table 1, proteinuria is equivalent or predominant in patients with Epstein syndrome; in contrast, hematuria is predominant, and macroscopic hematuria is often observed in patients with Alport syndrome much earlier than proteinuria. The second is the differences in the expression of causative genes in the glomeruli. The type IV collagen α5 chain gene responsible for Alport syndrome encodes an essential structural component of GBM; in contrast, NMMHC-IIA encoded by MYH9 is exclusively expressed in podocytes, renal tubular cells and endothelial cells, as shown in Figure 3. In general, GBM abnormalities could occur secondary to podocyte dysfunction. Taken together, we consider that the alterations of GBM in Epstein syndrome are a phenomenon secondary to the dysfunction NMMHC-IIA molecule in podocytes owing to MYH9 mutation. Kunishima et al.16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar reported that the abnormal distributions of NMMHC-IIA in blood neutrophils in cases with MYH9 disorders are classified into three types: type I, NMMHC-IIA is condensed into one or two granular masses; type II, NMMHC-IIA is present as granular masses of up to 20; type III, NMMHC-IIA is diffusely distributed as fine granules throughout the cytoplasm. Kunishima et al.16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar also indicated that the type of abnormal distribution of NMMHC-IIA is closely related to the site of the MYH9 mutation.16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar In all the cases in this study, NMMHC-IIA distribution in neutrophils was of type II (Figure 5 and Table 2). The abnormal distribution of NMMHC-IIA in Epstein–Fechtner syndrome could be directly associated with the pathogenesis in the kidney. Arrondel et al.17.Arrondel C. Vodovar N. Knebelmann B. et al.Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes.J Am Soc Nephrol. 2002; 13: 65-74PubMed Google Scholar showed the expression of NMMHC-IIA in podocytes, endocapillary cells, and proximal tubular cells in the human kidney. In this study, we show that NMMHC-IIA is expressed in the glomerulus, tubular cells including the distal tubule, loop of Henle, and the proximal tubule, endothelial cells of the interlobular arteries and arterioles, and peritubular capillaries. Ghiggeri et al.15.Ghiggeri G.M. Caridi G. Magrini U. et al.Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome).Am J Kidney Dis. 2003; 41: 95-104Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar discussed that the aggregation and compartmentation of NMMHC-IIA in podocytes might be associated with podocin dysfunction. In addition, there is another possibility. Two hereditary types of FSGS with an autosomal dominant trait are known, and one is caused by mutations in the gene encoding α-actinin-4 (ACTN4).18.Kaplan J.M. Kim S.H. North K.N. et al.Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.Nat Genet. 2000; 24: 251-256Crossref PubMed Scopus (1041) Google Scholar Several studies have indicated the following possible mechanisms: mutations in ACTN4 increased the ability of binding of mutated α-actinin-4 to actin filaments, alter their intracellular localization, and finally cause FSGS.19.Weins A. Kenlan P. Herbert S. et al.Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.J Am Soc Nephrol. 2005; 12: 3694-3701Crossref Scopus (142) Google Scholar, 20.Michaud J.L. Chaisson K.M. Parks R.J. et al.FSGS-associated alpha-actinin-4 (K256E) impairs cytoskeletal dynamics in podocytes.Kidney Int. 2006; 70: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Michaud et al.20.Michaud J.L. Chaisson K.M. Parks R.J. et al.FSGS-associated alpha-actinin-4 (K256E) impairs cytoskeletal dynamics in podocytes.Kidney Int. 2006; 70: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar showed that when mutated α-actinin-4 is expressed in cultured podocytes, and the localization of α-actinin-4 changes; that is, aberrant sequestering of α-actinin-4 impairs podocyte spreading and motility and decreases the number of peripheral projections. They suggested that these cytoskeletal derangements may underlie podocyte damage and foot process effacement. Recently, several studies have indicated that NMMHC-II has important roles in cell polarity, cell adhesion, and cell migration.21.Conti M.A. Adelstein R.S. Nonmuscle myosin II moves in new directions.J Cel Sci. 2008; 121 (Erratum in: J Cell Sci. 2008; 121(Part 3):404): 11-18Crossref PubMed Scopus (275) Google Scholar Podocytes are highly differentiated epithelial cells, and are connected to each other through a specific cell–cell adhesion molecule complex, that is, a slit diaphragm, which is crucial for glomerular filtration. NMMHC-IIA is considered to be located at the scaffolding underneath the plasma membrane and in the cytoplasm, and to have a role in maintaining and disassembling the adhesion junction complex.21.Conti M.A. Adelstein R.S. Nonmuscle myosin II moves in new directions.J Cel Sci. 2008; 121 (Erratum in: J Cell Sci. 2008; 121(Part 3):404): 11-18Crossref PubMed Scopus (275) Google Scholar It is plausible that mutated NMMHC-IIA would impair the function and structure of the slit diaphragm, which would result in proteinuria and the development of FSGS. It has been reported that human immunodeficiency virus-related or hypertension-related FSGS are common in the African-American populations. Recently, two groups have independently identified a highly significant association between the development of FSGS or ESRD and single-nucleotide polymorphisms in MYH9 in African-American individuals using an admixture-mapping linkage-disequilibrium genome scan method.11.Kopp J.B. Smith M.W. Nelson G.W. et al.MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.Nat Genet. 2008; 40: 1175-1184Crossref PubMed Scopus (587) Google Scholar, 12.Kao W.H. Klag M.J. Meoni L.A. et al.MYH9 is associated with nondiabetic end-stage renal disease in African Americans.Nat Genet. 2008; 40: 1185-1192Crossref PubMed Scopus (536) Google Scholar The development of ESRD was associated with hypertension, not with diabetes mellitus. This evidence strongly indicates that NMMHC-IIA is responsible for the development of not only Epstein–Fechtner syndrome, but also idiopathic FSGS. There is no information on why specific single-nucleotide polymorphisms in MYH9 increase the susceptibility of African-American individuals to FSGS or ESRD. Clarification of the pathophysiological mechanisms underlying the development of FSGS in Epstein–Fechtner syndrome would provide clues elucidating the molecular mechanisms underlying the development of FSGS. Just recently, Pecci et al.22.Pecci A. Granata A. Fiore C.E. et al.Renin-angiotensin system blockade is effective in reducing proteinuria of patients with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome).Nephrol Dial Transplant. 2008; 23: 2690-2692Crossref PubMed Scopus (59) Google Scholar have reported a favorable effect of ACEI and/or ARB on proteinuria in patients genetically diagnosed with Epstein–Fechtner syndrome. In this study, three cases among the nine enrolled were treated with ARB and/or ACEI. In case 2, administration of 20 mg of valsartan markedly reduced the amount of protein in the urine (Figure 3). In cases 4 and 7, ARB and ACEI partially reduced the amount of proteinuria. These findings, as well as those of Pecci et al., suggest the protective effect of ARB and ACEI on the kidney in cases with D1424H and N93K mutations. As the susceptibility to ESRD or FSGS caused by certain single-nucleotide polymorphisms in MYH9 in African Americans is also associated with hypertension, ARB and ACEI presumably showed a protective effect on the progression of renal dysfunction owing to their direct effects on podocytes. This is another important issue in the elucidation of the mechanisms underlying the development of FSGS related to NMMHC-IIA. In conclusion, in this study, we showed a rapid deterioration of renal function in cases with MYH9 R702 mutation, and the pathological findings in one case were consistent with FSGS; apparent changes in NMMHC-IIA expression in podocytes were observed in this patient. Further studies are required to elucidate the possible pathophysiological mechanisms by which podocyte dysfunction occurs because of R702 mutations in MYH9, which is cardinal in the development of FSGS in African-American populations. Such studies could provide us clues to the mechanisms underlying the development of idiopathic FSGS. We performed genetic analysis in approximately 100 patients suspected of having MYH9 disorders. Among those 100 patients, we selected all unrelated patients with R702 mutation and enrolled them in this study (Table 1). Some of the clinical and hematological data of patients 1, 2, 4, and 5 were previously published:23.Kunishima S. Yoshinari M. Nishio H. et al.Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations.Eur J Haematol. 2007; 78: 220-226Crossref PubMed Scopus (40) Google Scholar except for case 4, there were no symptoms of nephritis in these patients previously reported. The other cases are all new. Details of clinical data and courses, the treatment for nephritis, the treatment for ESRD, and the latest clinical data were obtained by the attending physician in each case. Ocular abnormalities and hearing disabilities were evaluated by ophthalmologists and otolaryngologists, respectively. The renal biopsy specimens from case 6 were evaluated by light microscopy and electron microscopy using conventional techniques. Immunohistochemical analysis was carried out as described below. Genetic analysis of MYH9 was approved by the institutional review boards of Nagoya Medical Center and each of the hospitals where the patients were enrolled, and was performed after informed consent was obtained from the patients and/or their parents. The IRB of the National Hospital Organization Nagoya Medical Center also approved the publication of the case reports and the obtained experimental data. Mutational analysis of MYH9 was performed as previously described.6.Kunishima S. Matsushita T. Kojima T. et al.Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions.J Hum Genet. 2001; 46: 722-729Crossref PubMed Scopus (98) Google Scholar Renal biopsy specimens from normal control and case 6 kidney samples were also subjected to immunohistochemical analysis. This was performed using 3 μm-thick sections of a paraffin-embedded sample. A renal specimen derived from a 51-year-old renal transplantation donor kidney, which was excised from the donor with immediate perfusion (0 h), was used as a control. Each renal section was autoclaved for 15 min at 121 °C in a citrate buffer of pH 6.0. After washing with water and phosphate-buffered saline, each section was incubated with an anti-NMMHC-IIA antibody (BT561, Biomedical Technologies, Stoughton, MA, USA, 1:100) for 2 h at room temperature. After washing, each section was further incubated with a secondary antibody (ENVISION, Dako, Kyoto, Japan) for 20 min. Subsequently, each section was treated with streptavidin-horseradish peroxidase and diaminobenzidine. The sections were then counterstained with hematoxylin. Immunofluorescence analysis was performed to evaluate the subcellular localization of NMMHC-IIA in peripheral blood neutrophils as previously described.16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar The cytoplasmic distribution patterns of NMMHC-IIA in neutrophils can be classified according to the number, size, and shape of accumulated NMMHC-IIA granules, into types I, II, and III. Type I comprises one or two large (0.5–2 μm), intensely stained, oval- to spindle-shaped cytoplasmic NMMHC-IIA-positive granules. Type II comprises up to 20 circular to oval cytoplasmic granules (≤1 μm). Type III appears as a speckled staining. The pattern of localization correlates with the site of MYH9 mutation. Mutations in exons 16, 26, and 30 are associated with type II localization.16.Kunishima S. Matsushita T. Kojima T. et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations.Lab Invest. 2003; 83: 115-122Crossref PubMed Scopus (126) Google Scholar This work was supported by grants to TS from the Japan Society for the Promotion of Science (20591271 and 18591183). This work was also supported by grants to SK from the Japan Society for the Promotion of Science (18591094 and 20591161), the Ministry of Health, Labor and Welfare (Grant for Child Health and Development 19C-2), the Charitable Trust Laboratory Medicine Foundation of Japan, the Mitsubishi Pharma Research Foundation, and the National Hospital Organization (network research grant for congenital thrombocytopenia). We thank Ms. Yoshimi Ito for her skillful technical assistance." @default.
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• W2071289299 title "Patients with Epstein–Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease" @default.
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