OMIA 000963-9913 : Syndactyly (mule foot) in Bos taurus

In other species: domestic cat , pig , sheep , dog , chicken , tammar wallaby , Swainson's hawk

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 212780 , 186100 , 186200 , 186300

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Cross-species summary: Fusion of the claws (cleats or digits). Occurs in one, two, three or (rarely) four legs.

Species-specific name: Mule foot disease; Haplotype HHM

Species-specific symbol: MFD; SY; HHM

Species-specific description: Syndactyly has been reported in many breeds of cattle in many countries. Most of the documentation, however, concerns its occurrence in US Holsteins, where, as a result of the siring of more than 60,000 calves by a bull who was subsequently shown to be a carrier, the disorder attracted considerable attention (Anon., 1967). The possibility that artificial selection favouring heterozygotes may have contributed to the unacceptably high frequency of the disorder was suggested by data showing that carrier females produced on average 2.1 pounds of butterfat and 298 pounds of milk more than homozygotes (Leipold et al., 1973). Progeny testing of males (Johnson et al., 1980) and females (Leipold and Peeples, 1981) was the main means of identifying carriers until Charlier et al. (1996) used a genome-wide set of DNA markers in an identity-by descent linkage study to show that the syndactyly gene is located on chromosome 15.

Mapping: Charlier et al. (1996) conducted a genome scan with 213 microsatellite markers genotyped on just 12 syndactylous (mule foot) animals and on a DNA pool of 10 unrelated non-affected animals from the same breed. Identity-by-descent mapping ("searching for shared homozygous haplotypes among affected individuals") identified a single region on each three chromosomes as being significant. Genotyping an additional 29 animals from the same pedigree, followed by a conventional linkage analysis, mapped the disorder to the telomeric end of chromosome BTA15.

In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) mapped this disorder to BTA15 at 76-82Mb (UMD 3.0 genome assembly), consistent with the results of Charlier et al. (1996).

Molecular basis: Duchesne et al. (2006) identified a CpG/ApT non-conservative substitution in exon 33 (C4863A, G4864T) of the bovine LRP4 gene, which segregates perfectly with the disorder in a Holstein pedigree.

Johnson et al. (2006) reported a different mutation in the same gene in Angus cattle: "a G to A transition at the first nucleotide in the splice donor site of intron 37 completely disables this splice site. The abnormal splicing that is caused by this mutation predicts the generation of a dysfunctional membrane-anchored receptor lacking the normal cytoplasmic domain."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
LRP4 LDL receptor related protein 4 Bos taurus 15 NC_037342.1 (76840799..76787303) LRP4 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

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
Angus Syndactyly (mule foot) LRP4 splicing UMD3.1 15 g.77667136 c.5385+1G>A "a G to A transition at the first nucleotide in the splice donor site of intron 37" 2006 16963222 Variant information kindly provided or confirmed by Hubert Pausch, including information from Additional Table 6 of Jansen et al. (2013) BMC Genomics201314:446 https://doi.org/10.1186/1471-2164-14-446
German Simmental Holstein Syndactyly (mule foot) LRP4 missense UMD3.1 15 g.77675440 c.4940C>T p.Pro1647Leu rs109636878 2007 17319939 Variant information kindly provided or confirmed by Hubert Pausch, including information from Additional Table 6 of Jansen et al. (2013) BMC Genomics201314:446 https://doi.org/10.1186/1471-2164-14-446; rsID gleaned from or confirmed by Table 1 of  Sharma et al. (2017) Animal Genetics 48(3):369-370
Holstein Syndactyly (mule foot) LRP4 indel, small (<=20) UMD3.1 15 g.77675516_77675517delCGinsAT c.4840_4841delCGinsAT p.(Asn1614_Gly1615delinsLysCys 2006 16859890 Variant information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)
German Simmental Holstein Syndactyly (mule foot) LRP4 missense UMD3.1 15 g.77682052G>A c.3571G>A p.Gly1191Ser 2007 17319939 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
German Simmental Holstein Syndactyly (mule foot) LRP4 missense UMD3.1 15 g.77686731G>A c.2719G>A p.Gly907Arg 2007 17319939 Variant information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)

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.
2019 Zepeda-Batista, J.L., Parra-Bracamonte, G.M., Núñez-Domínguez, R., Ramírez-Valverde, R., Ruíz-Flores, A., Zepeda-Batista, J.L., Parra-Bracamonte, G.M., Núñez-Domínguez, R., Ramírez-Valverde, R., Ruíz-Flores, A. :
Screening genetic diseases prevalence in Braunvieh cattle. Trop Anim Health Prod 51:25-31, 2019. Pubmed reference: 30014197. DOI: 10.1007/s11250-018-1655-y.
2016 Cole, J.B., Null, D.J., VanRaden, P.M. :
Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility. J Dairy Sci 99:7274-88, 2016. Pubmed reference: 27394947. DOI: 10.3168/jds.2015-10777.
2011 VanRaden, P.M., Olson, K.M., Null, D.J., Hutchison, J.L. :
Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J Dairy Sci 94:6153-61, 2011. Pubmed reference: 22118103. DOI: 10.3168/jds.2011-4624.
2007 Drögemüller, C., Leeb, T., Harlizius, B., Tammen, I., Distl, O., Höltershinken, M., Gentile, A., Duchesne, A., Eggen, A. :
Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4). BMC Genet 8:5, 2007. Pubmed reference: 17319939. DOI: 10.1186/1471-2156-8-5.
2006 Drogemuller, C., Distl, O. :
Genetic analysis of syndactyly in German Holstein cattle. Vet J 171:120-5, 2006. Pubmed reference: 16427589. DOI: 10.1016/j.tvjl.2004.09.009.
Duchesne, A., Gautier, M., Chadi, S., Grohs, C., Floriot, S., Gallard, Y., Caste, G., Ducos, A., Eggen, A. :
Identification of a doublet missense substitution in the bovine LRP4 gene as a candidate causal mutation for syndactyly in Holstein cattle. Genomics 88:610-621, 2006. Pubmed reference: 16859890. DOI: 10.1016/j.ygeno.2006.05.007.
Johnson, EB., Steffen, DJ., Lynch, KW., Herz, J. :
Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease. Genomics 88:600-609, 2006. Pubmed reference: 16963222. DOI: 10.1016/j.ygeno.2006.08.005.
Wöhlke, A., Kuiper, H., Distl, O., Drögemüller, C. :
The bovine aristaless-like homeobox 4 (ALX4) as a candidate gene for syndactyly. Cytogenet Genome Res 115:123-8, 2006. Pubmed reference: 17065792. DOI: 10.1159/000095231.
2005 Yeruhama, I., Goshen, T., Lahav, D., Perl, S. :
Simultaneous occurrence of epitheliogenesis imperfecta with syndactyly in a calf and a lamb. Aust Vet J 83:149-50, 2005. Pubmed reference: 15825625.
2004 Bahr, C., Drogemuller, C., Distl, O. :
[Case report: Syndactyly in German Holstein calves] Dtsch Tierarztl Wochenschr 111:473-6, 2004. Pubmed reference: 15648617.
1998 Leipold, H.W., Schmidt, G.L., Steffen, D.J., Vestweber, J.G.E., Huston, K. :
Hereditary syndactyly in Angus cattle Journal of Veterinary Diagnostic Investigation 10:247-254, 1998. Pubmed reference: 9683073.
1997 Fazili, M.U.R. :
Congenital unidactylism along with contracture of flexor tendon in a calf Indian Veterinary Journal 74:445, 1997.
1996 Charlier, C., Farnir, F., Berzi, P., Vanmanshoven, P., Brouwers, B., Vromans, H., Georges, M. :
Identity-by-descent mapping of recessive traits in livestock - application to map the bovine syndactyly locus to chromosome 15 Genome Research 6:580-589, 1996. Pubmed reference: 8796345.
1993 Agerholm, J.S., Basse, A., Christensen, K. :
Investigations on the occurrence of hereditary diseases in the Danish cattle population 1989-1991 Acta Veterinaria Scandinavica 34:245-253, 1993. Pubmed reference: 8310897.
1987 Hart-Elcock, L., Leipold, H.W., Baker, R. :
Hereditary bovine syndactyly: diagnosis in bovine fetuses Veterinary Pathology 24:140-147, 1987. Pubmed reference: 3033869.
1982 Alberda, G., Elgersma, A., Rozendaal, MG. :
[A case of syndactylia--'mule foot'--'horse's hoof'--in cattle] Tijdschr Diergeneeskd 107:800, 1982. Pubmed reference: 6294904.
1981 Leipold, H.W., Peeples, J.G. :
Progeny testing for bovine syndactyly. J Am Vet Med Assoc 179:69-70, 1981. Pubmed reference: 6265420.
1980 Baker, RD., Snider, GW., Leipold, HE., Johnson, JL. :
Embryo transfer tests for bovine syndactyly. Theriogenology 13:87, 1980. Pubmed reference: 16725457.
Johnson, JL., Leipold, HW., Snider, GW., Baker, RD. :
Progeny testing for bovine syndactyly. J Am Vet Med Assoc 176:549-50, 1980. Pubmed reference: 6245051.
1977 Guffy, M.M., Leipold, H.N. :
Radiological diagnosis of economically important genetic defects in cattle Journal of the American Veterinary Radiology Society 18:109-116, 1977.
Labik, K., Horin, P., Mikulas, L., Havrankova, J. :
Hereditarily conditioned cases of atresia ani, hernia umbilicalis and syndactylia in cattle Acta Veterinaria Brno 46:111-122, 1977.
Labik, K., Mikulas, L., Pelikan, J., Petrova, J. :
Syndactyly in cattle: a hereditary disease Veterinarstvi 27:118-119, 1977.
Leipold, H.W., Schalles, R. :
Genetic defects in cattle: transmission and control. Vet Med Small Anim Clin 72:80-5, 1977. Pubmed reference: 189478.
1976 Leipold, H.W., Guffy, M.M., Cook, J.E. :
Hereditary syndactyly in cattle Comparative Pathology Bulletin 8:3-4, 1976.
1975 Leipold, H.W. :
Genetics in veterinary medical research. Trans Kans Acad Sci 78:27-40, 1975. Pubmed reference: 205029.
Ojo, SA., Leipold, HW., Guffy, MM., Hibbs, CM. :
Syndactyly in Holstein-Friesian, Hereford, and crossbred Chianina cattle. J Am Vet Med Assoc 166:607-9, 1975. Pubmed reference: 164430.
1974 Leipold, HW., Dennis, SM., Huston, K., Dayton, AD. :
Hereditary bovine syndactyly. II. Hyperthermia. J Dairy Sci 57:1401-9, 1974. Pubmed reference: 4372255. DOI: 10.3168/jds.S0022-0302(74)85074-5.
1973 Leipold, H.W., Dennis, S.M., Huston, K. :
Syndactyly in cattle Veterinary Bulletin 43:399-403, 1973.
Leipold, H.W., Huston, K., Cooper, R.F., Farmer, E.L., Dennis, S.M., Dayton, A.D. :
Hereditary bovine syndactyly. I. Clinico-pathologic observations Giessener Beitrage zur Erbpathologie und Zuchthygiene 5:139-157, 1973.
1972 Leipold, HW., Dennis, SM., Huston, K. :
Congenital defects of cattle: nature, cause, and effect. Adv Vet Sci Comp Med 16:103-50, 1972. Pubmed reference: 4624930.
1971 Leipold, H.W., Dennis, S.M., Huston, K., Trotter, D., Adrian, R. :
Anatomy of hereditary bovine syndactyly. V. External description Giessener Beitrage zur Erbpathologie und Zuchthygiene 3:6-22, 1971.
1969 Adrian, R.W., Trotter, D.M., Leipold, H.W., Huston, K. :
Anatomy of hereditary bovine syndactylism. IV. Neurology Journal of Dairy Science 52:1441-1444, 1969. Pubmed reference: 4312938. DOI: 10.3168/jds.S0022-0302(69)86769-X.
Adrian, R.W, Trotter, D.M., Leipold, H.W. :
Digital muscles, nerves and vessels in syndactylous Holstein-Friesian cattle [abstract] Journal of Dairy Science 52:923 only, 1969.
Adrian, RW., Leipold, HW., Huston, K., Trotter, DM., Dennis, SM. :
Anatomy of hereditary bovine syndactylism. II. Muscles, tendons, and ligaments. J Dairy Sci 52:1432-5, 1969. Pubmed reference: 4312936. DOI: 10.3168/jds.S0022-0302(69)86767-6.
Adrian, RW., Trotter, DM., Leipold, HW., Huston, K. :
Anatomy of hereditary bovine syndactylism. 3. Angiology. J Dairy Sci 52:1436-40, 1969. Pubmed reference: 4312937.
Leipold, H.W., Huston, K., Guffy, M.M., Dennis, S.M. :
Syndactyly in an Aberdeen Angus Calf American Journal of Veterinary Research 30:1685-1687, 1969. Pubmed reference: 4308604.
Leipold, H.W., Huston, S.M., Dennis, S.M., Farmer, E.L. :
Hyperthermia in syndactylous Holstein-Friesian cattle [abstract] Journal of Dairy Science 52:923 only, 1969.
Leipold, HW., Adrian, RW., Huston, K., Trotter, DM., Dennis, SM., Guffy, MM. :
Anatomy of hereditary bovine syndactylism. I. Osteology. J Dairy Sci 52:1422-31, 1969. Pubmed reference: 4312935. DOI: 10.3168/jds.S0022-0302(69)86766-4.
1968 Borhoven, C. :
[Syn-polydactyly in cattle] Schweiz Arch Tierheilkd 110:532-5, 1968. Pubmed reference: 4307570.
Gruneberg, H., Huston, K. :
The development of bovine syndactylism. J Embryol Exp Morphol 19:251-9, 1968. Pubmed reference: 4297795.
Kraus, W. :
[Syn-polydactyly in an ox] Dtsch Tierarztl Wochenschr 75:120, 1968. Pubmed reference: 4304472.
Leipold, H.W. :
Syndactylism in cattle PhD thesis, Kanasa State University :, 1968.
1967 Anon. :
The A.I. dilemma Holstein-Friesian World 64:1394-1395, 1967.
1961 Farmer, E.L., Huston, K. :
Physiological aberrations in syndactylous cattle Journal of Animal Science 20:970, 1961.
Farmer, E.L., Huston, K. :
Physiological aberrations in syndactylous cattle Journal of Animal Science 20:970, 1961.
Huston, K., Eldridge, F.E., Mudge, J.W. :
Genetics of syndactylism in cattle Journal of Dairy Science 44:1197 only, 1961.
1956 Krolling, O. :
A morphogenetic and genetic interpretation of syndactyly in cattle Wiener Tierärztliche Monatsschrift 43:129-139, 1956.
1954 Motohashi, H. :
On twenty-six cases of syndactylous anomaly in the Nipponese improved cattle Tottori Society of Agricultural Science 10:212-236, 1954.
1951 Eldridge, F.E., Smith, W.H., McLeod, W.M. :
Syndactylism in Holstein Friesian cattle: its inheritance, description and occurrence Journal of Heredity 42:241-250, 1951.
1949 Singh, S., Bhattacharya, P. :
Inheritance of syndactylism in Hariana breed of cattle Indian Journal of Veterinary Sciences 19:153-159, 1949.
Singh, S., Tandon, R.K. :
A short note on calves with unbifurcated hooves Indian Journal of Veterinary Sciences 12:61 only, 1949.

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