In other species: domestic cat , horse , pig

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 306900 (trait) , 300746 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010604: hemophilia B

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1989

Cross-species summary: Also called hemophilia B, factor IX deficiency or Christmas disease. This is one of the two X-linked bleeding disorders, haemophilia A being the other. The fact that these two disorders are X-linked in all species reported to date provides strong support for Ohno's suggestion that the X chromosome has been highly conserved throughout evolution.

Species-specific symbol: F9

History: The first reports of this disorder in dogs were on a family of Cairn Terriers diagnosed at the Ontario Veterinary College, Guelph, by Mustard et al. (1960) and Rowsell et al. (1960). The Chapel Hill colony of haemophilia B dogs was established in 1966 from the Guelph animals or their descendants (Sabatino et al., 2012). A colony of Lhasa Apso dogs - the Auburn colony - was first reported by Mauser et al. (1996). Haemophilia B was the first canine disorder to be characterised at the DNA level.

Mapping: From the results of planned matings, Brinkhous et al. (1973) showed that although the genes for both haemophilia A and haemophilia B are on the X chromosome, they are inherited independently. A similar situation exists in human.

Molecular basis: The causative mutation for this disorder was discovered via the candidate gene approach, by Evans et al. (1989), who reported that the mutant allele in the Chapel Hill Cairn Terrier colony is c.1477G>A, resulting in the substitution of glutamic acid for glycine at codon 379 in the factor-IX peptide. This particular site has been highly conserved throughout evolution: there is a glycine at this position in factor IX from human, pig and cattle. Not surprisingly, therefore, this single amino-acid substitution profoundly alters the tertiary structure of the factor-IX molecule, to the extent that no functional factor IX can be detected, which is unusual for a missense mutation . In contrast, a different mutation causes the same disorder in Lhaso Apso dogs: Mauser et al. (1996) reported a deletion of bases 772-776 plus a C>T transition at base 777 in the Auburn colony. In an affected Labrador Retriever, Brooks et al. (1997) reported a deletion of the entire gene. Gu et al. (1999) reported two new mutations - an insertionin exon 8 and another deletion. Brooks et al. (2003) reported a 1.5kb LINE1 insertion in exon 5 associated with a mild form of the disorder. In Rhodesian Ridgebacks, Mischke et al. (2011) reported "a G-A missense mutation in exon 7. This mutation results in a glycine (GGA) to glutamic acid (GAA) exchange [G244E] in the catalytic domain of the haemophilic factor IX" Brenig et al. (2019) reported a mild form of Haemophilia B in a family of Hovawarts, likely caused by "a single nucleotide deletion in the F9 promoter. . . . The deletion is located 73 bp upstream of the F9 start codon in the conserved overlapping DNA binding sites of hepatocyte nuclear factor 4α and androgen receptor." Kuder et al. (2021) described a likely causal variant in the Newfoundland breed: "a single nucleotide insertion resulting in a frameshift in the last exon (NM_001003323.2:c.821_822insA), predicted to result in a premature stop codon (NP_001003323.1:p.Asn274LysfsTer23) with a loss of 178 of 459 amino acids . . . Both the purebred Newfoundland dam and her sister were heterozygous for the insertion. Five additional male offspring developed severe hemorrhage and were hemizygous for the F9 variant and/or had a prolonged aPTT. In contrast, other male littermates had normal aPTTs and no evidence of bleeding."

Clinical features: Haemophilia B is characterised by frequent and spontaneous bleeding into joints, muscles, and body cavities, such as the chest and abdomen, due to a deficiency in factor IX (FIX, F9) (Nichols et al., 2020). This can eventually lead to arthropathy associated with progressive cartilage damage, chronic pain, lameness, and eventually joint destruction (Nichols et al., 2020). Prolonged bleeding from minor wounds and haemorrhagic complications post-surgery may also be observed (Nichols et al., 2010). Disease can be classified into mild, moderate, or severe based on plasma FIX levels with 60-70% of patients having a moderate or severe form (Nichols et al., 2020). Animals with the severe form (<1% coagulation activity) can have bleeding episodes that are life threatening. Most carriers have a reduced FIX activity of 40-60% but do not exhibit spontaneous bleeding (Nakata et al., 2006). IT thanks DVM student Ruby Xu, who provided the basis of this contribution in May 2023.

Breeds: Airedale Terrier (Dog) (VBO_0200008), Alaskan Malamute (Dog) (VBO_0200017), American Cocker Spaniel (Dog) (VBO_0200038), American Pit Bull Terrier (Dog) (VBO_0200054), Beagle (Dog) (VBO_0200131), Bichon Frise (Dog) (VBO_0200163), Black and Tan Coonhound (Dog) (VBO_0200168), Cairn Terrier (Dog) (VBO_0200267), Chow Chow (Dog) (VBO_0200361), Doberman Pinscher (Dog) (VBO_0200442), French Bulldog (Dog) (VBO_0201455), German Shepherd Dog (Dog) (VBO_0200577), German Wirehaired Pointer (Dog) (VBO_0200602), Golden Retriever (Dog) (VBO_0200610), Hovawart (Dog) (VBO_0200674), Jack Russell Terrier (Dog) (VBO_0200724), Labrador Retriever (Dog) (VBO_0200800), Lhasa Apso (Dog) (VBO_0200824), Maltese Terrier (Dog) (VBO_0200859), Mixed Breed (Dog) (VBO_0200902), Newfoundland (Dog) (VBO_0200938), Old English Sheepdog (Dog) (VBO_0200969), Rhodesian Ridgeback (Dog) (VBO_0201135), Rottweiler (Dog) (VBO_0201143), Saint Bernard (Dog) (VBO_0201160), Scottish Terrier (Dog) (VBO_0201198), Sealyham Terrier (Dog) (VBO_0201200), Shih Tzu (Dog) (VBO_0201223), Weimaraner (Dog) (VBO_0201401), Wire Fox Terrier (Dog) (VBO_0201424).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: