In other species: dog , elk

Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 615553 (trait) , 605632 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2006

Species-specific name: Haplotype HHC

Species-specific symbol: CVM; HHC

Species-specific description: Complex vertebral malformation is an inherited syndrome in Holstein-Friesian cattle. CVM has been reported in aborted, premature born, stillborn and neonatal calves. Affected calves have a reduced weight, a misshapen backbone and tendon contractions in the legs. Several other malformations including heart malformations are associated with this syndrome. A DNA test is available in Denmark and the Netherlands. [Imke Tammen: 26 Jan 2002] From a study of 62,602 inseminations involving carrier bulls and daughters of carrier bulls, Nielsen et al. (2003) concluded that 77% of affected foetuses are aborted prior to day 260 of gestation, which is the earliest day from which cases have been diagnosed. This means that approximately 3/4 of affected foetuses are not diagnosed by necropsy [FN: 10 Jan 2003]

Mapping: By conducting a genome scan on 7 affected calves and their normal parents, each genotyped for 194 microsatellites, Thomsen et al. (2006) homozygosity-mapped this disorder to around 60cM on chromosome BTA3. Subsequent fine-mapping followed by comparative mapping of BACs containing the most likely candidate markers narrowed the candidate region of around 5.6Mb corresponding to human chromosome HSA1p21.2-21.3, which contains around 20 known or predicted genes. In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) confirmed the mapping of this disorder to BTA3 at 40-46Mb (UMD 3.0 genome assembly).

Markers: As shown by Fritz et al. (2013), it is very likely that the deleterious haplotypes HH5 and HH6 (which are closely linked to CVM) are reflecting the effect of the causal mutant for this disorder.

Molecular basis: Careful examination of the potential effects of mutations in any of the roughly 20 comparative candidate genes (see Mapping section), followed by mapping and sequencing of the most likely candidate gene, led Thomsen et al. (2006) to discover that CVM is caused by a missense mutation (c.559G>T) leading to V180F in the SLC35A3 gene [omia.variant:187], which encodes solute carrier family 35, member A3. Subsequent genotyping of this mutation in large numbers of other cattle confirmed that it is causal. (Mohammad Shariflou 11/11/2006; FN 12 June 2013). Bourneuf et al. (2017) detected SLC35A3 g.43418851G>T p.R25S as a de novo recessive potentially lethal mutation from an analysis of whole-genome-sequence of a Montbéliarde AI bull. No information was provided on the descendants of this bull.

Clinical features: Affected animals are either aborted any time during gestation, premature born, stillborn or in rare cases born alive. The weight of the animals is reduced. The defect is characterized by shortening of the cervical and thoracic parts of the vertebral column and symmetrical arthrogryphosis in the front and occasionally in the hind legs. In some cases further abnormalities, including protusion of the tongue, caudventrally displaced ears, protruding abdomen, umbilical hernia, palatochisis, dermoid attached to the conjunctiva, and brachygnathia superior, have been found [Imke Tammen: 26 Jan 2002]

Pathology: The histopathological findings are nonspecific. Radiological findings reveal that the affected calves have anomalies in the vertebral column (mainly cervical and thoracic vertebrae) including hemivertebrae, fused and misshapen vertebrae and ribs, scoliosis and vertebral synostosis. The skull and appendicular skeleton appear to be normal. Cardiac anomalies are reported in aproximately 50 % of the affected calves and involve interventricular septal defects, dextroposition of the aorta, eccentric hypertrophy of the right ventricle, and transposition of the aorta and the truncus pulmonalis [Imke Tammen: 26 Jan 2002]

Prevalence: CVM has so far been reported in Denmark, the USA, the UK and the Netherlands. The defect was traced back to an American AI bull that was formerly used extensively world wide and the prevalence of the disease is expected to be high [Imke Tammen: 26 Jan 2002]. Rafiq et al. (2023) "report the genotype and allelic frequency at rs438228855 [omia.variant:187] in SLC35A3 receptor gene ... in enrolled [Holstein Friesian, Sahiwal and cross cattle breed] Pakistani cattle. Our results, indicated that allelic and genotype frequency at rs438228855 varied non-significantly (P > 0.05) among the three enrolled cattle breed. GT (heterozygous) genotype was most abundant (0.54) followed by GG (wild type) genotype (0.45) while mutant genotype (TT) was not observed."

Genetic testing: Cases of CVM studied to date are due to a 559 G>T base substitution in SLC35A3 (solute carrier family 35 member 3). A DNA test is available from the Danish Institute of Agricultural Sciences [Imke Tammen: 26 Jan 2002]. In addition Kanae et al. (2005) developed Polymerase chain reaction-primer introduced restriction analysis (PCR-PIRA) as an alternative method for screening this mutation (Mohammad Shariflou11/11/2006).

Breeds: Holstein Friesian (Cattle) (VBO_0000239), Montbéliarde (Cattle) (VBO_0000306).
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: