Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome).
Macrothrombocytopenia with leukocyte inclusions is a rare autosomal dominant platelet disorder characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like leukocyte inclusions. A previous study mapped a locus for the disease on chromosome 22q12.3-q13.2 by genome-wide linkage analysis. In addition, the complete DNA sequence of human chromosome 22 allowed a positional candidate approach, and results here indicate that the gene encoding nonmuscle myosin heavy chain-A, NMMHC-A, is mutated in this disorder. Mutations were found in 6 of 7 Japanese families studied: 3 missense mutations, a nonsense mutation, and a one-base deletion resulting in a premature termination. Immunofluorescence studies revealed that NMMHC-A distribution in neutrophils appeared to mimic the inclusion bodies. These results provide evidence for the involvement of abnormal NMMHC-A in the formation of leukocyte inclusions and also in platelet morphogenesis.
Kunishima
S
S
First Department of Internal Medicine, Nagoya University School of Medicine, Showa-ku, Nagoya, Japan.
Kojima
T
T
Matsushita
T
T
Tanaka
T
T
Tsurusawa
M
M
Furukawa
Y
Y
Nakamura
Y
Y
Okamura
T
T
Amemiya
N
N
Nakayama
T
T
Kamiya
T
T
Saito
H
H
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000473:pathology*; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D007564:Japan; D007962:Leukocytes / Q000648:ultrastructure*; D008297:Male; D020409:Molecular Motor Proteins; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D009504:Neutrophils / Q000737:chemistry / Q000648:ultrastructure; D010375:Pedigree; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics* / Q000473:pathology
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains