Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene.
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.
Seri
Marco
M
Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genoa, Italy.
Savino
Maria
M
Bordo
Domenico
D
Cusano
Roberto
R
Rocca
Bianca
B
Meloni
Ilaria
I
Di Bari
Filomena
F
Koivisto
Pasi A
PA
Bolognesi
Martino
M
Ghiggeri
Gian Marco
GM
Landolfi
Raffaele
R
Balduini
Carlo L
CL
Zelante
Leopoldo
L
Ravazzolo
Roberto
R
Renieri
Alessandra
A
Savoia
Anna
A
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000473:pathology; D003638:Deafness / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D020409:Molecular Motor Proteins; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D009393:Nephritis / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains