Categories: Craniofacial phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 235730 (trait) , 605802 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific symbol: PMS

History: This disorder was first described by Capitan et al. (2012), as a result of screening the entire French cattle population for novel horn-development abnormalities, which identified a "Charolais bull (V.), born to horned parents, that never developed normal horns but instead small horny scabs and for which the polled progeny displayed severe additional symptoms."

Inheritance: As reported by Capitan et al. (2012), "male-specific lethality during the first third of gestation" gives rise to sex-ratio distortion. The authors noted that this is "the first case of male-specific lethality associated with an autosomal locus in a non-murine mammalian species".

Mapping: Capitan et al. (2012) conducted a genome scan with a 50,000 SNP chip on the proband Charolais bull V, "19 unaffected progeny, three affected daughters and their dams". This highlighted a 2.8Mb region on chromosome BTA2 which showed a cluster of loci showing errors of Mendelian inheritance, suggestive of a deletion.

Molecular basis: Genotyping of the three affected daughters with a 777,000 SNP chip, combined with whole-genome sequencing of one of the affected daughters, enabled Capitan et al. (2012) to identify the causative mutation as a 3.7Mb deletion encompassing the genes ARHGAP15, GTDC1 and ZEB2. Comparison with the homologous human disorder (see MIM entry above) implied that the syndrome is primarily due to the deletion of ZEB2. Gerhke et al. (2020) identified "an 11-bp deletion (AC_000159.1:g.52364063_52364073del; Del11) in the second exon of ZEB2 gene as the causal mutation for . . .[a] de novo polled condition [in a "polled bull (FV-Polled1) born to horned parents, indicating a de novo origin of this polled condition"]. We predicted that the deletion would shorten the protein product of ZEB2 by almost 91%. Moreover, we showed that all animals carrying Del11 mutation displayed symptoms similar to Mowat-Wilson syndrome (MWS) in humans, which is also associated with genetic variations in ZEB2. The symptoms in cattle include delayed maturity, small body stature and abnormal shape of skull."

Clinical features: As reported by Capitan et al. (2012), this disorder's "clinical spectrum includes polledness (complete agenesis of horns), facial dysmorphism, growth delay, chronic diarrhea, premature ovarian failure, and variable neurological and cardiac anomalies".

Breeds: Charolais (Cattle) (VBO_0000177), Simmental (Cattle) (VBO_0000380).
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: