Epstein syndrome

Another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene

Marco Seri, Maria Savino, Domenico Bordo, Roberto Cusano, Bianca Rocca, Ilaria Meloni, Filomena Di Bari, Pasi A. Koivisto, Martino Bolognesi, Gian Marco Ghiggeri, Raffaele Landolfi, Carlo L. Balduini, Leopoldo Zelante, Roberto Ravazzolo, Alessandra Renieri, Anna Savoia

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Epstein syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA (MYH9). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.

Original languageEnglish
Pages (from-to)182-186
Number of pages5
JournalHuman Genetics
Volume110
Issue number2
DOIs
Publication statusPublished - Feb 2002

Fingerprint

Myosin Heavy Chains
Kidney
Mutation
Genes
Blood Platelets
MYH9-Related Disorders
Nonmuscle Myosin Type IIA
Smooth Muscle Myosins
Nephritis
Inclusion Bodies
Missense Mutation
Amino Acid Substitution
Myosins
Hearing Loss
Sulfhydryl Compounds
Codon
Disulfides
Thrombocytopenia
Hearing

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Epstein syndrome : Another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene. / Seri, Marco; Savino, Maria; Bordo, Domenico; Cusano, Roberto; Rocca, Bianca; Meloni, Ilaria; Di Bari, Filomena; Koivisto, Pasi A.; Bolognesi, Martino; Ghiggeri, Gian Marco; Landolfi, Raffaele; Balduini, Carlo L.; Zelante, Leopoldo; Ravazzolo, Roberto; Renieri, Alessandra; Savoia, Anna.

In: Human Genetics, Vol. 110, No. 2, 02.2002, p. 182-186.

Research output: Contribution to journalArticle

Seri, M, Savino, M, Bordo, D, Cusano, R, Rocca, B, Meloni, I, Di Bari, F, Koivisto, PA, Bolognesi, M, Ghiggeri, GM, Landolfi, R, Balduini, CL, Zelante, L, Ravazzolo, R, Renieri, A & Savoia, A 2002, 'Epstein syndrome: Another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene', Human Genetics, vol. 110, no. 2, pp. 182-186. https://doi.org/10.1007/s00439-001-0659-1
Seri, Marco ; Savino, Maria ; Bordo, Domenico ; Cusano, Roberto ; Rocca, Bianca ; Meloni, Ilaria ; Di Bari, Filomena ; Koivisto, Pasi A. ; Bolognesi, Martino ; Ghiggeri, Gian Marco ; Landolfi, Raffaele ; Balduini, Carlo L. ; Zelante, Leopoldo ; Ravazzolo, Roberto ; Renieri, Alessandra ; Savoia, Anna. / Epstein syndrome : Another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene. In: Human Genetics. 2002 ; Vol. 110, No. 2. pp. 182-186.
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T2 - Another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene

AU - Seri, Marco

AU - Savino, Maria

AU - Bordo, Domenico

AU - Cusano, Roberto

AU - Rocca, Bianca

AU - Meloni, Ilaria

AU - Di Bari, Filomena

AU - Koivisto, Pasi A.

AU - Bolognesi, Martino

AU - Ghiggeri, Gian Marco

AU - Landolfi, Raffaele

AU - Balduini, Carlo L.

AU - Zelante, Leopoldo

AU - Ravazzolo, Roberto

AU - Renieri, Alessandra

AU - Savoia, Anna

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N2 - Epstein syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA (MYH9). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.

AB - Epstein syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA (MYH9). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.

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