title: A 3.7 Mb deletion encompassing ZEB2 causes a novel polled and multisystemic syndrome in the progeny of a somatic mosaic bull.
abstract: Polled and Multisystemic Syndrome (PMS) is a novel developmental disorder occurring in the progeny of a single bull. Its clinical spectrum includes polledness (complete agenesis of horns), facial dysmorphism, growth delay, chronic diarrhea, premature ovarian failure, and variable neurological and cardiac anomalies. PMS is also characterized by a deviation of the sex-ratio, suggesting male lethality during pregnancy. Using Mendelian error mapping and whole-genome sequencing, we identified a 3.7 Mb deletion on the paternal bovine chromosome 2 encompassing ARHGAP15, GTDC1 and ZEB2 genes. We then produced control and affected 90-day old fetuses to characterize this syndrome by histological and expression analyses. Compared to wild type individuals, affected animals showed a decreased expression of the three deleted genes. Based on a comparison with human Mowat-Wilson syndrome, we suggest that deletion of ZEB2, is responsible for most of the effects of the mutation. Finally sperm-FISH, embryo genotyping and analysis of reproduction records confirmed somatic mosaicism in the founder bull and male-specific lethality during the first third of gestation. In conclusion, we identified a novel locus involved in bovid horn ontogenesis and suggest that epithelial-to-mesenchymal transition plays a critical role in horn bud differentiation. We also provide new insights into the pathogenicity of ZEB2 loss of heterozygosity in bovine and humans and describe the first case of male-specific lethality associated with an autosomal locus in a non-murine mammalian species. This result sets PMS as a unique model to study sex-specific gene expression/regulation.
authors.affiliation: INRA, UMR1313 Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France. aurelien.capitan@jouy.inra.fr
authors.forename: Aurélien
authors.initials: A
authors.lastname: Capitan
authors.forename: Aurélie
authors.initials: A
authors.lastname: Allais-Bonnet
authors.forename: Alain
authors.initials: A
authors.lastname: Pinton
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marquant-Le Guienne
authors.forename: Daniel
authors.initials: D
authors.lastname: Le Bourhis
authors.forename: Cécile
authors.initials: C
authors.lastname: Grohs
authors.forename: Stéphan
authors.initials: S
authors.lastname: Bouet
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Clément
authors.forename: Laura
authors.initials: L
authors.lastname: Salas-Cortes
authors.forename: Eric
authors.initials: E
authors.lastname: Venot
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chaffaux
authors.forename: Bernard
authors.initials: B
authors.lastname: Weiss
authors.forename: Arnaud
authors.initials: A
authors.lastname: Delpeuch
authors.forename: Guy
authors.initials: G
authors.lastname: Noé
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Rossignol
authors.forename: Sarah
authors.initials: S
authors.lastname: Barbey
authors.forename: Dominique
authors.initials: D
authors.lastname: Dozias
authors.forename: Emilie
authors.initials: E
authors.lastname: Cobo
authors.forename: Harmonie
authors.initials: H
authors.lastname: Barasc
authors.forename: Aurélie
authors.initials: A
authors.lastname: Auguste
authors.forename: Maëlle
authors.initials: M
authors.lastname: Pannetier
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Deloche
authors.forename: Emeline
authors.initials: E
authors.lastname: Lhuilier
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouchez
authors.forename: Diane
authors.initials: D
authors.lastname: Esquerré
authors.forename: Gérald
authors.initials: G
authors.lastname: Salin
authors.forename: Christophe
authors.initials: C
authors.lastname: Klopp
authors.forename: Cécile
authors.initials: C
authors.lastname: Donnadieu
authors.forename: Céline
authors.initials: C
authors.lastname: Chantry-Darmon
authors.forename: Hélène
authors.initials: H
authors.lastname: Hayes
authors.forename: Yves
authors.initials: Y
authors.lastname: Gallard
authors.forename: Claire
authors.initials: C
authors.lastname: Ponsart
authors.forename: Didier
authors.initials: D
authors.lastname: Boichard
authors.forename: Eric
authors.initials: E
authors.lastname: Pailhoux
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D000818:Animals; D020029:Base Pairing / Q000235:genetics*; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000473:pathology; D006733:Horns / Q000473:pathology; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D012867:Skin / Q000473:pathology; D013577:Syndrome
chemical_list: D012097:Repressor Proteins