Korean J Hematol.  2006 Mar;41(1):16-27. 10.5045/kjh.2006.41.1.16.

Clinical Characteristics of Autosomal Dominant Giant Platelet Syndromes and Mutation Analysis of MYH9

• Kook H
• Nam HS
• Baek HJ
• Kim YO
• Eom GH
• Kee HJ
• Cho D
• Shin MG
• Lee JJ
• Kim HJ
• Kook H
• Hwang TJ

• KMID: 2252323
• DOI: http://doi.org/10.5045/kjh.2006.41.1.16

Abstract

BACKGROUND: The autosomal dominant giant platelet syndromes (GPS), characterized by triads of giant platelets, thrombocytopenia, and Dohle-like leukocyte inclusions are caused by MYH9 mutation, a gene encoding the nonmuscle myosin heavy chain-IIA. This study was aimed to identify the Korean GPS patients and to define clinical findings and molecular characteristics on them.
METHODS
After taking a family history, platelets were counted using hematologic autoanalyzer and peripheral blood smear (PBS) was examined for platelet size and number, and the presence of leukocyte inclusions. Mutation of MYH9 was studied from mononuclear cells from PB by direct sequencing of previously known 8 exons after PCR amplification of genomic DNA.
RESULTS
Twenty patients from 5 unrelated families were diagnosed as GPS. Giant platelets, greater than red cells on PBS, were found to be 3.1% of platelet (range, 1~11%). The median platelet count was 61,000/microliter. Inclusion bodies were found in 3 families. Two families had previously reported mutations. Family I had Arg1944Ter in exon 40, located in the tail portion of myosin, while Family IV had Lys373Asn in exon 10, located in the proximal portion of myosin head. The mutations were found only in affected patients, but not in normal siblings or unrelated families.
CONCLUSION
In this study, we identified several families with autosomal dominant GPS. Two families had known MYH9 mutations, Arg1944Ter and Lys373Asn. The search for unknown mutations in the remaining families as well as study of protein structural and functional alteration seems to be necessary for further delineation of these rare genetic disorders.

Keyword

MYH9 mutation; Giant platelet syndrome; Arg1944Ter; Lys373Asn

MeSH Terms

Bernard-Soulier Syndrome
Blood Platelets*
DNA
Exons
Genes, vif
Head
Humans
Inclusion Bodies
Leukocytes
Myosins
Platelet Count
Polymerase Chain Reaction
Siblings
Thrombocytopenia
DNA
Myosins

Figure

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  Fig. 1 (A) Blood smear shows thrombocytopenia with giant platelets. (B) Döhle-like inclusion body in leukocyte in patient 3C (arrow) (Wright's Giemsa×1,000).

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  Fig. 2 Pedigrees of the Family II (A), Family III (B) and Family V (C). All the families show the autosomal dominant inheritance spanning 3 generations.

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  Fig. 3 Pedigree and electropherograms showing genetic alterations of MYH9 gene in the Family I. The candidate exons of MYH9 in the affected patients and in their normal siblings were subjected to genotyping after PCR amplification. (A) Pedgree shows the typical autosomal dominant trait of penetration. (B, C) Electropherogram showing the alteration of single nucleotide in the 40th exon in the proband white arrow in A & B), comparing with the normal sibling (black arrow in A & C). Note that equal amounts of thymidine (T) and cytidine (C) were reported as N, suggesting two different alleles are present. No other mutations were found in the patient. And this mutation was present only in this family.

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  Fig. 4 Pedigree and electropherograms showing genetic alterations of MYH9 gene in the Family IV. The candidate exons of MYH9 in the affected patients and in their normal siblings were subjected to genotyping after PCR amplification. (A) Pedgree shows the typical autosomal dominant trait of penetration. (B, C) Electropherogram showing the alteration of single nucleotide in the 10th exon in the proband (white arrow in A & B), comparing with the normal sibling (black arrow in A & C). Genotyping of 10th exon shows the patient has two different alleles of cytidine (C) and guanosine (G).

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  Fig. 5 The linear protein structure was obtained from pfam (www.sanger.ac.uk) and the relative location of the mutations was pointed out. One mutation from the Family IV was located in the head portion of the myosin, while that of the Family I was at the tail portion of the protein.

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