OMIA 000437-9940 : Haemophilia A in Ovis aries

In other species: domestic cat , dog , horse , pig , cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 306700

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2010

Cross-species summary: Also called factor VIII deficiency. Impaired coagulability of the blood, with a consequential strong tendency to bleed, due to a deficiency of clotting factor VIII. Since the gene for this factor is located on the X chromosome, the disorder is expected to be X-linked. As with haemophilia B, this expectation has been confirmed in all species of mammal in which the disorder has been reported. In humans, there are hundreds of different mutations that give rise to haemophilia A. In domesticated animals, the disorder has been reported in a large range of species.

Species-specific symbol: HA

History: None of the haemophiliac sheep described by Neuenschwander and Pliska (1990) and studied by Neuenschwander et al. (1992), Neuenschwander and Pliska (1994) and Backfisch et al. (1994) survived, and hence this line of sheep had become extinct. However, a few straws of semen had been retained, and from these, Porada et al. (2010) were able to recreate the haemophiliac line of sheep, which should be a valuable animal model.

Mapping: Using in situ hybridization with a 3-kb fragment of human F8C cDNA, Backfisch et al. (1994) mapped the ovine F8C gene to Xq24-q33.

Markers: In Swiss sheep, an RFLP detected with a 1.8-kb SstI/KpnI fragment of the cDNA of the human F8C gene, detects a 5.8 kb band which is associated with the mutant allele (Backfisch et al., 1994).

Molecular basis: By sequencing the obvious candidate gene (F8), Porada et al. (2010) "identified an 11 bp region in exon 14 that differed between the wild-type and the hemophiliac. Importantly, this difference introduced a premature stop codon at base position 3112–4 in exon 14, as is seen in some human HA patients. This mutation also included a single nucleotide insertion-induced frame shift, creating five additional stop codons within the next 183 bp, precluding protein translation past this point, and providing a molecular explanation for the severe phenotype".

Breed: Swiss Alpine.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
F8 coagulation factor VIII Homo sapiens X NC_000023.11 (155022723..154835788) F8 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Swiss Alpine Haemophilia A F8 indel, small (<=20) c.3107del10ins11 2010 19943872

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2016 Yen, C.T., Fan, M.N., Yang, Y.L., Chou, S.C., Yu, I.S., Lin, S.W. :
Current animal models of hemophilia: the state of the art. Thromb J 14:22, 2016. Pubmed reference: 27766048. DOI: 10.1186/s12959-016-0106-0.
2012 Porada, C.D., Almeida-Porada, G. :
Treatment of Hemophilia A in Utero and Postnatally using Sheep as a Model for Cell and Gene Delivery. J Genet Syndr Gene Ther S1:, 2012. Pubmed reference: 23264887. DOI: 10.4172/2157-7412.S1-011.
Zakas, P.M., Gangadharan, B., Almeida-Porada, G., Porada, C.D., Spencer, H.T., Doering, C.B. :
Development and Characterization of Recombinant Ovine Coagulation Factor VIII. PLoS One 7:e49481, 2012. Pubmed reference: 23152911. DOI: 10.1371/journal.pone.0049481.
2011 Porada, C.D., Sanada, C., Kuo, C.J., Colletti, E., Mandeville, W., Hasenau, J., Zanjani, E.D., Moot, R., Doering, C., Spencer, H.T., Almeida-Porada, G. :
Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC. Exp Hematol 39:1124-1135.e4, 2011. Pubmed reference: 21906573. DOI: 10.1016/j.exphem.2011.09.001.
2010 Porada, C.D., Sanada, C., Long, C.R., Wood, J.A., Desai, J., Frederick, N., Millsap, L., Bormann, C., Menges, S.L., Hanna, C., Flores-Foxworth, G., Shin, T., Westhusin, M.E., Liu, W., Glimp, H., Zanjani, E.D., Lozier, J.N., Pliska, V., Stranzinger, G., Joerg, H., Kraemer, D.C., Almeida-Porada, G. :
Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A. J Thromb Haemost 8:276-85, 2010. Pubmed reference: 19943872. DOI: 10.1111/j.1538-7836.2009.03697.x.
1994 Backfisch, W., Neuenschwander, S., Giger, U., Stranzinger, G., Pliska, V. :
Carrier detection of ovine hemophilia A using an RFLP marker, and mapping of the factor VIII gene on the ovine X-chromosome Journal of Heredity 85:474-478, 1994. Pubmed reference: 7995928.
Neuenschwander, S., Pliska, V. :
Factor VIII in blood plasma of haemophilic sheep: Analysis of clotting time-plasma dilution curves Haemostasis 24:27-35, 1994. Pubmed reference: 7959353.
1992 Neuenschwander, S., Kisslingalbrecht, L., Heiniger, J., Backfisch, W., Stranzinger, G., Pliska, V. :
Inherited Defect of Blood Clotting Factor-VIII (Haemophilia- A) in Sheep Thrombosis and Haemostasis 68:618-620, 1992. Pubmed reference: 1455410.
1990 Neuenschwander, S., Pliska, V. :
Hemophilia in Sheep and the Use of Sheep in Blood Coagulation Research Journal of Animal Breeding and Genetics-Zeitschrift Fur Tierzuchtung und Zuchtungsbiologie S5:155-164, 1990.

Edit History


  • Created by Frank Nicholas on 16 Jul 2005
  • Changed by Frank Nicholas on 03 Dec 2012