title: Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium.
abstract: 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 ('Döhle-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 carboxy-terminal 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.
authors.affiliation: Laboratory of Molecular Genetics, Institute G. Gaslini, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Seri
authors.forename: R
authors.initials: R
authors.lastname: Cusano
authors.forename: S
authors.initials: S
authors.lastname: Gangarossa
authors.forename: G
authors.initials: G
authors.lastname: Caridi
authors.forename: D
authors.initials: D
authors.lastname: Bordo
authors.forename: C
authors.initials: C
authors.lastname: Lo Nigro
authors.forename: G M
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: R
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: M
authors.initials: M
authors.lastname: Savino
authors.forename: M
authors.initials: M
authors.lastname: Del Vecchio
authors.forename: M
authors.initials: M
authors.lastname: d'Apolito
authors.forename: A
authors.initials: A
authors.lastname: Iolascon
authors.forename: L L
authors.initials: LL
authors.lastname: Zelante
authors.forename: A
authors.initials: A
authors.lastname: Savoia
authors.forename: C L
authors.initials: CL
authors.lastname: Balduini
authors.forename: P
authors.initials: P
authors.lastname: Noris
authors.forename: U
authors.initials: U
authors.lastname: Magrini
authors.forename: S
authors.initials: S
authors.lastname: Belletti
authors.forename: K E
authors.initials: KE
authors.lastname: Heath
authors.forename: M
authors.initials: M
authors.lastname: Babcock
authors.forename: M J
authors.initials: MJ
authors.lastname: Glucksman
authors.forename: E
authors.initials: E
authors.lastname: Aliprandis
authors.forename: N
authors.initials: N
authors.lastname: Bizzaro
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: J A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001791:Blood Platelet Disorders / Q000235:genetics* / Q000473:pathology; D002386:Cataract / Q000235:genetics; D002645:Chickens; D002892:Chromosomes, Human, Pair 22; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000473:pathology*; D008958:Models, Molecular; D020409:Molecular Motor Proteins; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D009218:Myosins / Q000737:chemistry / Q000235:genetics; D009393:Nephritis / Q000235:genetics; D009504:Neutrophils / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains; D009218:Myosins