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

Mü llerian inhibiting substance (MIS), a secreted glycoprotein in the transforming growth factor-beta family of growth factors, mediates regression of the Mü llerian ducts during embryonic sex differentiation in males. In persistent Mü llerian duct syndrome (PMDS), rather than undergoing involution, the Mü llerian 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.

Classical and Molecular Cytogenetics of Disorders of Sex Development in Domestic Animals

“…This phenotypic condition is fully superimposed on human syndrome PMDS (OMIM 261550). The genetic cause of this abnormal phenotype has been found recently linked to the AMH type 2 receptor, confirming the data described some years ago in humans [Imbeaud et al, 1996;Wu et al, 2009]. Up to now there is no evidence of male pseudohermaphroditism in dogs caused by either androgen production failure (defects in the 5-alpha reductase gene) or androgen insensitivity (deficiency in the X-linked androgen receptor gene).…”

Ambiguous Genitalia in a Fertile, Unilaterally Cryptorchid Male Miniature Schnauzer Dog

“…5 Bilaterally cryptorchid dogs are sterile, whereas dogs with PMDS and bilateral scrotal testes are usually fertile, despite lower than expected sperm counts. 13 Unilaterally cryptorchid affected males typically have lower than normal sperm counts 13 ; despite unilateral cryptorchidism, the dog described in this report was able to breed successfully.…”

Comparative cytogenetic mapping of three genes involved in sex determination in four species of the family <i>Canidae</i>

“…It is commonly known that mutations of these genes may cause intersexuality in pet species (Lyle, 2007) as well as in other mammals. In spite of the fact that the intersexual phenotype is quite often reported in the dog, to date only one causative mutation has been described (Wu et al, 2009). In this report chromosomal localization of three genes (SOX9, AMH and AR) in four canids is presented.…”

“…Knowledge on monogenetic hereditary diseases in the dog is quite advanced (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omia&tool=toolbar); however, only one gene mutation responsible for the intersexual syndrome was identified (Wu et al, 2009). In the reference family (Miniature Schnauzer × Beagle), where the Persistent Müllerian Duct Syndrome (PMDS) was identified, the causative mutation in an a priori selected candidate gene (MISRII) was searched for.…”