Inherited diseases of Holstein cattle: Story so far in Turkey

Inherited diseases are caused by recessive alleles proceed from increased inbreeding in Holstein cattle population. Bovine leucocyte adhesion deficiency (BLAD), deficiency of uridine monophosphate synthase enzyme (DUMPS), complex vertebral malformation (CVM), factor XI deficiency (FXID) and bovine citrulinaemia (BC) are the most frequent inherited diseases in Holstein cattle population. The prevalence for carriers of BLAD, DUMPS, CVM, FXID and BC diseases were reported highest in Denmark (21.5%), USA (1.2%), Japan (32.5%), Turkey (18%) and Australia (13%) respectively. Moreover the highest prevalence for carriers of BLAD, CVM and FXID were reported as 2.2%, 3.4% and 18% respectively in Turkey so far. Neither DUMPS nor BC carriers were identified in Turkey so far. However further studies are required in order to identify the provinces that have risks for mutant alleles of inherited diseases in Turkey. Determining the carrier animals and exclude them from breeding is the only solution for eradication studies of inherited diseases.


Inherited diseases of Holstein cattle: Story so far in Turkey
Holstein is one of the mostly used cattle breed in dairy farming. In order to gain genetic improvement in Holstein cattle breeding, elite sires have been used intensively all around the world with artificial insemination (AI). The frequency of undesired recessive mutant alleles that cause to various inherited diseases, have been increased in Holstein cattle population as an outcome of inbreeding. Genetic diseases are usually caused by the inheritance of an absent or non-functional mutant gene. The homozygous animals for recessive mutant allele are affected by the disease. The heterozygous animals are responsible to transfer the inherited diseases to next generation and they are names as carriers. Mating between two carrier animals would genetically produce 25% of healthy, 50% of carrier and 25% of affected offspring. The development of molecular methods made possible to display the mutant alleles and identification of carriers. The aim of this review is to clarify the most frequent inherited disease of Holstein cattle and to notice their carrier prevalence determined so far in Turkey.

Introduction
To cite this article: Avanus, K., & Altınel, A. (2017). Inherited diseases of Holstein cattle: Story so far in Turkey. Journal of Istanbul Veterinary Sciences, 1(2), 40-46. Abbreviated Title: J Ist Vet Sci helps endothelial adhesion, decreases on leucocyte's cell surface. The disease is caused by a point mutation converts adenine to guanine in 383th nucleotide of CD18 encoding gene located in bovine chromosome 1.

Deficiency of uridine monophosphate synthase (DUMPS)
The uridine monophosphate synthase (UMPS) enzyme catalyzes converting orotic acid to uridine monophosphate in mammalian cells. Pyrimidine nucleotides compose the structure of DNA and RNA and UMPS is necessary for pyrimidine nucleotides synthesis. Deficiency of uridine monophosphate synthase (DUMPS) is caused by a single point mutation that substitutes cytosine to timin and leads to a premature stop codon at codon 405 within exon 5 of UMPS gene on bovine chromosome 1 (Patel et al., 2006). Embryos homozygous for mutant allele that cause to DUMPS usually die early in gestation, they do not survive to birth. After 40 days of conception the embryos are usually aborted or reabsorbed, which leads to repeated breeding problems. Carriers have only half the normal activity of uridine monophosphate synthase, but they are phenotypically normal. The activity of the enzyme UMP synthase in in the liver, spleen, kidney, muscle and mammary gland is relatively decreased to about half of the normal value. Also carriers excrete an increased level of orotic acid in milk and urine. The distributor of the DUMPS carrier allele were Happy Herd Beautician and Skokie Sensation Ned (Kaminski et al., 2005). The prevalence of DUMPS carriers was reported in USA (1.2%, Shanks et al., 1990) and Argentine (0.96% bulls, 0.11% cows, Poli et al., 1996). No carriers were identified in Poland (Kaminski et al., 2005) and Czech Republic (Citek et al., 2006).

Factor XI deficiency (FXID)
Factor XI is one of the blood clotting proteins. Factor XI Deficiency (FXID) may result in anemia with prolonged bleeding from the umbilical cord. Marron et al. (2004) have determined an insertion of a 76 bp segment into exon 12 of FXI gene (AT(A)28TAAAG(A) 26GGAAATAATAATTCA) located on bovine chromosome 27 that was the causative mutation for FXID. The long strings of adenine (A) bases in the insertion, contains a stop codon and inhibits the fulllength protein synthesis. Affected cows frequently have reduced reproduction performance, pink-colored colostrum, and susceptibility to diseases such as mastitis, metritis and pneumonia. Cattle that are homozygous and heterozygous for FXID mutant allele, might have lower calving and survival rates, since the estrous cycle of the affected cows is characterized by reduced follicular development and a slow process of luteolysis. The affected animals may survive for years with no other clinical signs in herd. Therefor FXID may have a significant economic loss on the dairy industry . The prevalence of FXID was reported from USA (1.19%, Marron et al., 2004), Japan (2.5%, Ghanem et al.,2005), India (0.2%, Rajeah et al., 2007) and Czech Republic (0.36%, Citek et al., 2008).

Bovine citrullinaemia (BC)
Bovine citrullinaemia (BC) was firstly reported by Healey et al. (1990) after importation of semen from the US sire Linmack Kriss King to Australian Holstein population. The disease causes arginosuccinate synthetase (ASS) enzyme deficiency inhibits the conversion of citrulline to arginosuccinate in the course of urea metabolism. This situation causes to accumulation of citrulline, which is a more toxic product than ammonia during the process of urogenesis. The patient accumulates a high amount of citrulline in blood, cerebrospinal fluid, eye fluids and brain tissue. Bovine citrullinaemia is caused by a substitution of cytosine to thymine at codon 86 within exon 5 of the gene coding for ASS (Padeeri et al., 1999). Affected cattle by BC appear normal after birth. However the second day of life, affected calf looks depressed and there is no feed intake. The third day, calf often seen aimlessly roaming or standing with their head pressed against a wall. The disease progresses rapidly between the third and fifth day. The calf appears to be blind and finally collapses. Homozygous calves die during the first seven days of life. The prevalence of BC carriers were reported from USA (0.3%, Robinson et al., 1993), Australia (13%, Healge et al., 1996), and China (0.16%, Li et al., 2011). The BC carriers were not found in Germany (Grupe et al., 2006), Czech Republic (Citek et al., 2006) and India (Patel et al., 2006).

The prevalence of carriers of Holstein inherited diseases in Turkey
There were various studies performed in order to determine the carriers of inherited diseases in Holstein cattle reared in different provinces of Turkey. The prevalence of carriers for these inherited diseases were summarized in Table 1.
The variations of prevalence's of carriers among each diseases (BLAD, FXID and CVM) might be sourced from the differences in sampling sizes, farms and regions in each study. Absence of mutant alleles of DUMPS and BC does not mean that Turkey is free from these diseases. Further studies should be performed in order to scan the mutant alleles in Holstein population of Turkey. Since if a genetic disease has finally been detected, the frequency of the recessive allele might have already increased in the population. In order to eradicate the inherited diseases, breeders in Turkey should always have a pedigree record, newborns should be registered carefully and defected calves' parents should be tested for suspected inherited diseases.

Conclusion
The wide use of only a few elite sires has enhanced to increase in autosomal resessif inherited diseases with AI all around the world in Holstein cattle population. The most frequently reported inherited disease in Holstein cattle were BLAD, DUMPS, CVM, FXID and BC. After improvement of molecular methods, various studies were performed all around the world in order to identify the carriers, exclude them from breeding and eradicate the inherited diseases from Holstein cattle breeding. The highest prevalance of BLAD, DUMPS, CVM, FXID and BC carriers were found in Denmark (21.5% Jorgensen et al., 1993), USA (1.2% Shanta et al., 2002), Japan (32.5% Nagahata et al., 2002), Turkey (18% Kormaz Ag aog lu et al., 2015) and Australia (13%, Healge et al., 1996) respectively. The highest prevalance for BLAD, CVM and FXID carriers were 2.2%, (Meydan et al., 2009), 6.6% (Avanus & Altınel, 2016 b ) and 18% (Kormaz Ag aog lu et al., 2015) respectively in Turkey. Among BLAD, DUMPS, CVM, FXID and BC diseases, FXID had the highest prevalance of carriers, but BLAD was the most studied one by the researchers from all around the world. Further studies should be performed in different regions and provinces for screening and controlling mutant alleles of BLAD, CVM and FXID diseases and before concluding that Turkey is null from DUMPS and BC mutant alleles.