title: Genotype-phenotype correlation in MYH9-related thrombocytopenia.
abstract: Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype-phenotype relationship.
authors.affiliation: Department of Medicine, Duke University Medical Center and Hematology/Oncology, Durham Veterans Affairs Hospital, Durham, NC 27705, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Dong
authors.forename: Sufeng
authors.initials: S
authors.lastname: Li
authors.forename: Núria
authors.initials: N
authors.lastname: Pujol-Moix
authors.forename: Naomi L C
authors.initials: NL
authors.lastname: Luban
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Shin
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.forename: Arlette
authors.initials: A
authors.lastname: Ruiz-Saez
authors.forename: Judit
authors.initials: J
authors.lastname: Demeter
authors.forename: Scott
authors.initials: S
authors.lastname: Langdon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelley
mesh_terms: D001791:Blood Platelet Disorders / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004252:DNA Mutational Analysis; D005799:Genes, Dominant; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics; D020409:Molecular Motor Proteins / Q000235:genetics*; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype; D013921:Thrombocytopenia / Q000235:genetics*
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains