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

Possibly relevant human trait(s) and/or gene(s) (MIM number): 612598 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2012

History: The history of RING fingers is most unusual. In 1991 Hanson et al. (Genomics, 10, 417-424) reported the discovery of four new genes of unknown function within the human major histocompatibility complex (HLA), which is the "engine room" of the immune response. These four new genes were designated RING 1-4, where RING stood for Really Interesting New Gene! Two years later, Lovering et al. (1993; PNAS 90, 2112-2116) reported that these genes encode a zinc-finger-like protein motif that occurs in many proteins and which is associated with DNA binding. Not surprisingly, they named this motif the "RING finger"! Now, with the report by Sartelet et al. (2012), we have the first case of a disorder resulting from a mutation in a RING finger gene.

Inheritance: This form of proportionate dwarfism is autosomal recessive. However, because up to 1/3 of affected calves die of severe inflammation (mainly pneumonia) within 6 months of birth, the expected autosomal recessive segregation ratios are not seen in surviving dwarf calves (Sartelet et al., 2012). The disorder is lethal in the sense that affected animals are never bred.

Molecular basis: Sartelet et al. (2012) identified the causative mutation as a "c124-­2A>G splice variant in intron 1 of the RNF11 gene". This gene encodes RING finger protein 11, which is a key regulator in the A20 complex of the inflammatory response.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Prevalence: Sartelet et al. (2012) reported the surprising result "that 26% of healthy Belgian Blue animals" are carriers of the mutant allele, corresponding to a mutant-allele frequency of 13%. This is extraordinalrily high for an allele that is, in effect, lethal. These same authors provided evidence supporting selection favouring heterozygotes as being the most likely explanation. The traits undergoing such selection remain to be determined.

Breed: Belgian Blue (Cattle) (VBO_0000139).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: