OMIA 000827-9913 : Myeloencephalopathy, progressive degenerative (Weaver syndrome) in Bos taurus

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

Species-specific name: Weaver syndrome; Haplotype BHW

Species-specific symbol: BHW

Mapping: In one of the very early genome scans, Georges et al. (1993) genotyped 33 affected Brown Swiss, plus (where possible) their sires, dams and normal siblings, with "82 multisite haplotypes . . . , 38 variable number of tandem repeat markers . . . , and 233 bovine dinucleotide microsatellites". The 78th microsatellite tested in two-point linkage analysis, namely TGLA116, showed a significant recombination fraction of 3% with the disorder. No other markers showed any linkage. Subsequent somatic-cell-hybrid mapping enabled TGLA116 to be allocated to bovine synteny group 13.

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 BTA4 at 45-56Mb (UMD 3.0 genome assembly).

By conducting a GWAS on 20 carriers and 51 normal Brown Swiss, each genotyped with the Illumina BovineHD assay (yielding 733,937 informative SNPs), and subsequent fine-mapping, McClure et al. (2013) refined the mapping of this disorder to a 252 kb haplotype on chromosome BTA4, which will provide greater accuracy for carrier detection.

In their table of reduced-fertility haplotypes, Cole et al. (2014) list the "Weaver" haplotype as haplotype BHW (for Brown Swiss/Haplotype/Weaver).

Molecular basis: Kunz et al. (2016) reported a likely causal mutation as "a missense mutation (p.S568N, c.G1703A; [Chr4: 49,878,773 bp, rs800397662]) in the PNPLA8 gene that encodes patatin-like phospholipase domain containing 8".

Prevalence: As reported by Kunz et al. (2016), "Genotyping for the candidate causal mutation in a random sample of 2334 current Braunvieh animals suggested a frequency of the Weaver allele of 0.26 %"

Genetic testing: Using the powerful tool of imputation from 50K SNP genotypes, McClure et al. (2013) reported that <7,500 Brown Swiss have now been characterised as carriers or non-carriers of the haplotype described in the Mapping section (above). Identification of a likely causal mutation by Kunz et al. (2016) (see Molecular basis section) has the potential to replace the haplotype test with a specific SNP test.

Breed: Brown Swiss.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PNPLA8 patatin like phospholipase domain containing 8 Bos taurus 4 NC_037331.1 (49638458..49588035) PNPLA8 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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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
Brown Swiss Carora Progressive degenerative myeloencephalopathy (Weaver syndrome) PNPLA8 missense UMD3.1 4 g.49878773G>A c.1703G>A p.S568N rs800397662 2016 26992691 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed 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.
2018 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 :, 2018. 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.
Kunz, E., Rothammer, S., Pausch, H., Schwarzenbacher, H., Seefried, F.R., Matiasek, K., Seichter, D., Russ, I., Fries, R., Medugorac, I. :
Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle. Genet Sel Evol 48:21, 2016. Pubmed reference: 26992691. DOI: 10.1186/s12711-016-0201-5.
2014 Cole, J.B. , VanRaden, P.M., Null, D.J., Hutchison, J.L., Cooper, T.A., Hubbard, S.M. :
Haplotype tests for recessive disorders that affect fertility and other traits. AIP RESEARCH REPORT GENOMIC3 (09-13); http://aipl.arsusda.gov/reference/recessive_haplotypes_ARR-G3.html :, 2014.
2013 McClure, M., Kim, E., Bickhart, D., Null, D., Cooper, T., Cole, J., Wiggans, G., Ajmone-Marsan, P., Colli, L., Santus, E., Liu, G.E., Schroeder, S., Matukumalli, L., Van Tassell, C., Sonstegard, T. :
Fine mapping for Weaver syndrome in Brown Swiss cattle and the identification of 41 concordant mutations across NRCAM, PNPLA8 and CTTNBP2. PLoS One 8:e59251, 2013. Pubmed reference: 23527149. DOI: 10.1371/journal.pone.0059251.
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.
2009 Manatrinon, S., Egger-Danner, C., Baumung, R. :
Estimating lethal allele frequencies in complex pedigrees via gene dropping approach using the example of Brown Swiss cattle Archiv fur Tierzucht 52:230-242, 2009.
2008 de Oliveira, P.C.L., Coelho, H.E., de Medeiros, A., Rieck, S.E., de Souza, J.M., Alvarenga, R.R. :
Degenerative progressive hereditary mieloencefalopathy (Weaver Syndrome) in Gir calves Ciencia Rural 38:161-165, 2008.
2002 Shan, XS., Zhang, Y., Li, N. :
[Effects of several microsatellite DNA loci on milk production in dairy cattle] Yi Chuan Xue Bao 29:430-3, 2002. Pubmed reference: 12043571.
2001 Abdallah, M.B., Speidel, S., Oberg, E., DeNise, S. :
Development of a physical map of bovine chromosome 4 that contains the gene responsible for Bovine Progressive Degenerative Myeloencephalopathy (PDME) Journal of Dairy Science 84:Suppl 1, p. 338 (abstract), 2001.
Speidel, S., Oberg, E., Abdallah, M.B., DeNise, S. :
Genetic analysis of candidate genes for Weaver Syndrome in Brown Swiss Cattle Journal of Dairy Science 84:Suppl. 1, page 339 (abstract), 2001.
1994 Lidauer, M., Essl, A. :
Estimation of the Frequencies for Recessive Lethal Genes for Spinal Muscular Atrophy, Arachnomelia and Weaver in the Austrian Braunvieh Population Zuchtungskunde 66:54-65, 1994.
Tenhumberg, H., Trela, T., Matzke, P., Averdunk, G., Dirksen, G. :
Bovine progressive degenerative myeloencephalopathy (''Weaver syndrome'') in Brown Swiss x Braunvieh cattle: Reproductive features and embryo transfer Berliner und Munchener Tierarztliche Wochenschrift 107:400-404, 1994. Pubmed reference: 7717957.
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.
Doll, K., Trela, T., Matzke, P., Dahme, E., Hafner, A., Dirksen, G. :
Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) in Brown Swiss Cross Braunvieh Cattle - Symptomatology, Course, Hematology and Cerebrospinal Fluid Analysis Tierarztliche Umschau 48:467, 1993.
Georges, M., Dietz, A.B., Mishra, A., Nielsen, D., Sargeant, L.S., Sorensen, A., Steele, M.R., Zhao, X.Y., Leipold, H.W., Womack, J.E., Lathrop, M. :
Microsatellite Mapping of the Gene Causing Weaver Disease in Cattle Will Allow the Study of an Associated Quantitative Trait Locus Proceedings of the National Academy of Sciences of the United States of America 90:1058-1062, 1993. Pubmed reference: 8430074.
Troyer, D., Cash, W., Leipold, H.W. :
Skeletal Muscle of Cattle Affected with Progressive Degenerative Myeloencephalopathy American Journal of Veterinary Research 54:1084-1087, 1993. Pubmed reference: 8368603.
1992 Baldrighi, M., Scanziani, E., Perotti, G. :
La mieloencefalopatia progressiva degenerativa bovina (sindrome “weaver”) della razza Bruna. Documenti Veterinari :73-75, 1992.
Oyster, R., Leipold, H.W., Troyer, D., Cash, W. :
Electron Microscopic Studies of Bovine Progressive Degenerative Myeloencephalopathy in Brown Swiss Cattle Journal of Veterinary Medicine Series A - Zentralblatt Fur Veterinarmedizin Reihe A - Physiology Pathology Clinical Medicine 39:600-608, 1992.
Oyster, R., Leipold, H.W., Troyer, D., Cash, W., Johnson, D. :
Histochemical and Morphometric Studies of Peripheral Muscle in Bovine Progressive Degenerative Myeloencephalopathy of Brown Swiss Cattle Journal of Veterinary Medicine Series A - Zentralblatt Fur Veterinarmedizin Reihe A - Physiology Pathology Clinical Medicine 39:321-327, 1992.
1990 Elhamidi, M., Leipold, H.W., Cook, J.E. :
Ultrastructural Changes in Brown Swiss Cattle Affected with Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) Journal of Veterinary Medicine Series A-Zentralblatt Fur Veterinarmedizin Reihe A-Physiology Pathology Clinical Medicine 37:729-736, 1990. Pubmed reference: 2127493.
Hoeschele, I., Meinert, T.R. :
Association of Genetic Defects with Yield and Type Traits - The Weaver Locus Effect on Yield Journal of Dairy Science 73:2503-2515, 1990. Pubmed reference: 2258494. DOI: 10.3168/jds.S0022-0302(90)78936-9.
1988 Baird, JD., Sarmiento, UM., Basrur, PK. :
Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) in Brown Swiss Cattle in Canada: A Literature Review and Case Report. Can Vet J 29:370-377, 1988. Pubmed reference: 17423028.
Leipold, H.W. :
Straight talk on Weavers Brown Swiss Bulletin :30-32, 1988.
1987 Braun, U., Ehrensperger, F., Bracher, V. :
[The Weaver syndrome in cattle. Clinical, biochemical and pathologico-anatomic studies in a Braunvieh/Brown Swiss cow with bovine progressive degenerative myeloencephalopathy] Tierarztl Prax 15:139-44, 1987. Pubmed reference: 3617038.
1985 Aitchison, CS., Westfall, JA., Leipold, HW., Kelly, PT. :
Ultrastructural alterations of motor cortex synaptic junctions in Brown Swiss cattle with weaver syndrome. Am J Vet Res 46:1733-6, 1985. Pubmed reference: 4037501.
Stuart, LD., Leipold, HW. :
Lesions in bovine progressive degenerative myeloencephalopathy ("Weaver") of Brown Swiss cattle. Vet Pathol 22:13-23, 1985. Pubmed reference: 3976130.
1984 Hansen, K.M. :
Weaver-syndromet hos amerikansk Brunkvaeg [Weaver syndrome in Brown Swiss cattle] Dansk Veterinartidsskrift 67:425-429, 1984.
1983 Stuart, L., Leipold, H.W. :
Bovine progressive degenerative myeloencephalopathy (“weaver”) of Brown Swiss cattle I: Epidemiology. Bovine Practice 18:129-132, 1983.
Stuart, L., Leipold, H.W. :
Bovine progressive degenerative myeloencephalopathy (“weaver”) of Brown Swiss cattle II: Clinical and laboratory findings. Bovine Practice 18:133-146, 1983.
1973 Leipold, HW., Blaugh, B., Huston, K., Edgerly, CG., Hibbs, CM. :
Weaver syndrome in Brown Swiss cattle: clinical signs and pathology. Vet Med Small Anim Clin 68:645-7, 1973. Pubmed reference: 4488646.

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