TY - JOUR
T1 - Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes
AU - Seri, Marco
AU - Cusano, Roberto
AU - Gangarossa, Simone
AU - Caridi, Gianluca
AU - Bordo, Domenico
AU - Nigro, Cristiana Lo
AU - Ghiggeri, Gian Marco
AU - Ravazzolo, Roberto
AU - Suvino, Maria
AU - Del Vecchio, Maria
AU - D'Apolito, Maria
AU - Iolascon, Achille
AU - Zelante, Leopoldo L.
AU - Savoia, Anna
AU - Balduini, Carlo L.
AU - Noris, Patrizia
AU - Magrini, Umberto
AU - Belletti, Simona
AU - Heath, Karen E.
AU - Babcock, Melanie
AU - Glucksman, Marc J.
AU - Aliprandis, Elias
AU - Bizzaro, Nicola
AU - Desnick, Robert J.
AU - Martignetti, John A.
PY - 2000/9
Y1 - 2000/9
N2 - The autosomal dominant, giant-platelet disorders, May-Hegglin anomaly (MHA; MIM 155100), Fechtner syndrome (FTNS; MIM 153640) and Sebastian syndrome (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions ('Dohle-like' bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8-10), which is expressed in platelets and upregulated during granulocyte differentiation. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxyterminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.
AB - The autosomal dominant, giant-platelet disorders, May-Hegglin anomaly (MHA; MIM 155100), Fechtner syndrome (FTNS; MIM 153640) and Sebastian syndrome (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions ('Dohle-like' bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8-10), which is expressed in platelets and upregulated during granulocyte differentiation. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxyterminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.
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U2 - 10.1038/79063
DO - 10.1038/79063
M3 - Article
C2 - 10973259
AN - SCOPUS:0033812573
VL - 26
SP - 103
EP - 105
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 1
ER -