title: A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent Müllerian duct syndrome.
abstract: Müllerian inhibiting substance (MIS), a secreted glycoprotein in the transforming growth factor-beta family of growth factors, mediates regression of the Müllerian ducts during embryonic sex differentiation in males. In persistent Müllerian duct syndrome (PMDS), rather than undergoing involution, the Müllerian ducts persist in males, giving rise to the uterus, fallopian tubes, and upper vagina. Genetic defects in MIS or its receptor (MISRII) have been identified in patients with PMDS. The phenotype in the canine model of PMDS derived from the miniature schnauzer breed is strikingly similar to that of human patients. In this model, PMDS is inherited as a sex-limited autosomal recessive trait. Previous studies indicated that a defect in the MIS receptor or its downstream signaling pathway was likely to be causative of the canine syndrome. In this study, the canine PMDS phenotype and clinical sequelae are described in detail. Affected and unaffected members of this pedigree are genotyped, identifying a single base pair substitution in MISRII that introduces a stop codon in exon 3. The homozygous mutation terminates translation at 80 amino acids, eliminating much of the extracellular domain and the entire transmembrane and intracellular signaling domains. Findings in this model could enable insights to be garnered from correlation of detailed clinical descriptions with molecular defects, which are not otherwise possible in the human syndrome.
authors: Pediatric Endocrine Division, Department of Pediatrics and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Xiufeng
authors: X
authors: Wu
authors: Shengqin
authors: S
authors: Wan
authors: Shashikant
authors: S
authors: Pujar
authors: Mark E
authors: ME
authors: Haskins
authors: Donald H
authors: DH
authors: Schlafer
authors: Mary M
authors: MM
authors: Lee
authors: Vicki N
authors: VN
authors: Meyers-Wallen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004285:Dogs; D005808:Genes, Recessive; D005835:Genitalia / Q000473:pathology; D006059:Gonadal Dysgenesis / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D018000:Receptors, Peptide / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor