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Original Article

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Blood Res 2013; 48(3):

Published online September 25, 2013

https://doi.org/10.5045/br.2013.48.3.206

© The Korean Society of Hematology

Sequence variation data of F8 and F9 genes in functionally validated control individuals: implications on the molecular diagnosis of hemophilia

Ja Young Seo1,#, Mi-Ae Jang1, Hee-Jung Kim1, Ki-O Lee2, Sun-Hee Kim1, and Hee-Jin Kim1*

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1Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

2Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.

Correspondence to : Correspondence to Hee-Jin Kim, M.D. Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: +82-2-3410-2710, Fax: +82-2-3410-2719, heejinkim@skku.edu

Received: March 28, 2013; Revised: July 16, 2013; Accepted: July 24, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background

The F8 and F9 genes encode for coagulation factor VIII (FVIII) and FIX, respectively, and mutations in these genes are the genetic basis of hemophilia A/B. To determine whether a sequence variation in F8/F9 is a disease-causing mutation, frequency data from a control population is needed. This study aimed to obtain data on sequence variation in F8/F9 in a set of functionally validated control chromosomes of Korean descent.

Methods

We re-sequenced F8 and F9 from DNA samples of 100 Korean male control individuals with normal PT, aPTT, and FVIII activity. PCR and direct sequencing analyses were performed using primer pairs to cover all coding regions and the flanking intronic sequences.

Results

Thirteen individuals (13%) were hemizygous for sequence variations in the coding region of F8. Six (6%) had c.3780C>G (p.Asp1260Glu), five (5%) had c.3864A>C (p.Ser1288=). One each individual (1%) had c.4794G>T (p.Glu1598Asp) and c.5069 A>G (p.Glu1690Gly). Asp1260Glu and Ser1288= were known SNPs (rs1800291 and rs1800292, respectively). Glu1598Asp was assigned as a missense mutation in public databases (HGMD and HAMSTeRS), and Glu1690Gly was a novel variation. Based on the normal FVIII activities in control individuals carrying these variations (109% and 148%, respectively), they were considered to be rare SNPs. No variation was observed in F9 of control individuals.

Conclusion

A significant proportion of control individuals carried sequence variations in F8, but not in F9. These results can be used as a reference dataset for molecular diagnosis of hemophilia A and B, particularly in Korea.

Keywords Hemophilia, F8, F9, Sequence variation, Control population, Korea

Article

Original Article

Blood Res 2013; 48(3): 206-210

Published online September 25, 2013 https://doi.org/10.5045/br.2013.48.3.206

Copyright © The Korean Society of Hematology.

Sequence variation data of F8 and F9 genes in functionally validated control individuals: implications on the molecular diagnosis of hemophilia

Ja Young Seo1,#, Mi-Ae Jang1, Hee-Jung Kim1, Ki-O Lee2, Sun-Hee Kim1, and Hee-Jin Kim1*

1Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

2Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.

Correspondence to: Correspondence to Hee-Jin Kim, M.D. Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: +82-2-3410-2710, Fax: +82-2-3410-2719, heejinkim@skku.edu

Received: March 28, 2013; Revised: July 16, 2013; Accepted: July 24, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The F8 and F9 genes encode for coagulation factor VIII (FVIII) and FIX, respectively, and mutations in these genes are the genetic basis of hemophilia A/B. To determine whether a sequence variation in F8/F9 is a disease-causing mutation, frequency data from a control population is needed. This study aimed to obtain data on sequence variation in F8/F9 in a set of functionally validated control chromosomes of Korean descent.

Methods

We re-sequenced F8 and F9 from DNA samples of 100 Korean male control individuals with normal PT, aPTT, and FVIII activity. PCR and direct sequencing analyses were performed using primer pairs to cover all coding regions and the flanking intronic sequences.

Results

Thirteen individuals (13%) were hemizygous for sequence variations in the coding region of F8. Six (6%) had c.3780C>G (p.Asp1260Glu), five (5%) had c.3864A>C (p.Ser1288=). One each individual (1%) had c.4794G>T (p.Glu1598Asp) and c.5069 A>G (p.Glu1690Gly). Asp1260Glu and Ser1288= were known SNPs (rs1800291 and rs1800292, respectively). Glu1598Asp was assigned as a missense mutation in public databases (HGMD and HAMSTeRS), and Glu1690Gly was a novel variation. Based on the normal FVIII activities in control individuals carrying these variations (109% and 148%, respectively), they were considered to be rare SNPs. No variation was observed in F9 of control individuals.

Conclusion

A significant proportion of control individuals carried sequence variations in F8, but not in F9. These results can be used as a reference dataset for molecular diagnosis of hemophilia A and B, particularly in Korea.

Keywords: Hemophilia, F8, F9, Sequence variation, Control population, Korea

Fig 1.

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Figure 1.

The distribution of factor VIII activity levels of the carriers and non-carriers of 2 common polymorphisms Asp1260Glu (A) and Ser1288=(B) among the control individuals. The upper/lower ends and the inner lines of the boxes correspond to the upper/lower quartiles and median values, respectively. Circles represent factor VIII activity values. The lines from each box extend from the minimum to the maximum values, excluding outlying values displayed as a separate circle.

Blood Research 2013; 48: 206-210https://doi.org/10.5045/br.2013.48.3.206

Fig 2.

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Figure 2.

Alignment of the F8 peptide sequences in human and other species using ClustalW2. Note that the Glu1598 and Glu1690 residues are not conserved across mammalian and non-mammalian species.

Blood Research 2013; 48: 206-210https://doi.org/10.5045/br.2013.48.3.206

Table 1 . Four sequence variations of the F8 gene observed in functionally validated male control individuals of Korean descent..

a)Reference interval of FVIII activity: 55.150% for blood type O, 77.205% for blood type non-O..

Abbreviations: MAF, minor allele frequency; NA, not applicable; FVIII, coagulation factor VIII; SD, standard deviation..
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