Categories: Limbs / fins / digit / tail phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612264 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2009

Species-specific name: Crooked tail syndrome

Species-specific symbol: CTS

Species-specific description: "Affected animals have a crooked tail and shortened head, growth retardation, extreme muscularity and spastic paresia, although some characteristics show variable penetrance. CTS is not lethal per se, but causes substantial economic losses due to growth retardation and treatment." (Charlier et al., 2008)

Mapping: In a pioneering use of tens of thousands of SNP markers ("using either the 25K Affymetrix SNP panel or a custom-made 60K Illumina panel"), Charlier et al. (2008) identified a single 2.42 Mb region on BTA19 in which 8 affected calves were significantly more homozygous for the same allele at each of many SNPs, when compared with 14 normal controls.

Molecular basis: Following hot on the heels of the mapping of this disorder, Fasquelle et al. (2009) showed it to be due to a frameshifting 2-bp deletion (c.2904-2905delAG) in the MRC2 gene (encoding mannose receptor C type 2). Following the publication of the 2009 paper, 18 new cases with exactly the same clinical signs were detected, and were all shown by Sartelet et al. (2012) to be NOT homozygous for this (recessive) mutation, but instead to be heterozygous for this mutation. How could this be? Why would heterozygotes for a recessive disorder show all the clinical signs usually seen in homozygotes? Detailed investigation by Sartelet et al. (2012) of these 18 cases showed each of them to be a compound heterozygote for the c.2904-2905delAG mutation and a newly identified mutation, namely c.1906T>C, in the same gene. The former mutation results in no functional peptide, and the latter mutation results in illegitimate oligomerization of the peptide. Consequently, compound heterozygotes for these two mutations have no fully functional gene product, and hence are affected with the disorder.

Genetic testing: The detection of a second mutation by Sartelet et al. (2012) in the same (MRC2) gene in the same breed of cattle (described in the Molecular basis section above) provides a cautionary tale for the provision of genetic testing for disorders: clients must always be warned that available tests may not detect all relevant mutations. In other words, there is always the chance that the same or similar clinical signs can result from a mutation that has not yet been detected.

Breeds: Belgian Blue (Cattle) (VBO_0000139), Brown Swiss (Cattle) (VBO_0000166).
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: