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,
From the * Pediatric Endocrine Division,
Department of Pediatrics and Cell Biology, University of Massachusetts Medical
School, Worcester, Massachusetts; the Baker
Institute for Animal Health and the Department
of Biomedical Sciences, College of Veterinary Medicine, Cornell University,
Ithaca, New York; and the Department of
Pathobiology, School of Veterinary Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania.
| Correspondence to: Vicki N. Meyers-Wallen, Baker Institute for Animal Health, Hungerford Hill Road, Cornell University, Ithaca, NY 14853 (e-mail: vnm1{at}cornell.edu). |
| Received for publication May 1, 2008; accepted for publication August 20, 2008. |
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Abstract |
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Key words: Dog, anti-Müllerian hormone, AMH type II receptor (AMHR2), Müllerian duct regression
A defect in MIS signaling causes retained rudimentary Müllerian structures or an infantile uterus and Fallopian tubes, a condition found in humans (Brook et al, 1973; Sloan and Walsh, 1976) as well as a number of other species such as dogs (Brown et al, 1976), cattle (Jost, 1965), goats (Haibel and Rojko, 1990), and cats (Schulman and Levine, 1989). In infants and children, this is typically identified at the time of surgery for cryptorchidism or inguinal hernia and is termed persistent Müllerian duct syndrome (PMDS; Brook et al, 1973; Sloan and Walsh, 1976; Josso et al, 1983). The testes can be bilaterally undescended, or one can descend and carry the contralateral testis into the same scrotum, a condition called transverse testicular ectopia.
In patients with PMDS, the mode of inheritance is primarily autosomal recessive. Molecular studies have identified genetic defects in either MIS or MISRII in over 80% of patients with PMDS (Guerrier et al, 1989; Imbeaud et al, 1994, 1995; Messika-Zeitoun et al, 2001; Belville et al, 2004). Those patients with MIS gene defects have unmeasurable or low serum concentrations of MIS and have been found to have a number of different mutations spanning the gene. In contrast, mutations of MISRII are more conserved, with a common 27-bp deletion in exon 10 in the serine-threonine kinase domain, accounting for 25% of known receptor defects (Imbeaud et al, 1996). The MISRII mutations identified thus far either affect ligand binding or abrogate kinase activity of the receptor with no mutations of the transmembrane region (exon 4) identified as yet.
Canine PMDS has been reported as an inherited disorder in 2 breeds: the miniature schnauzer in the United States (Brown et al, 1976; Marshall et al, 1982; Meyers-Wallen et al, 1989) and the basset hound in Europe (Nickel et al, 1992). The causative genetic defect has not been identified in either breed. The canine model derived from the PMDS miniature schnauzer has a phenotype that is strikingly similar to that of human PMDS (Meyers-Wallen et al, 1989). In the PMDS model, the expression of MIS mRNA and protein were no different in testes of PMDS embryos than those of normal embryos during the critical period for Müllerian duct regression (Meyers-Wallen et al, 1991, 1993). Furthermore, in studies for which a semi-quantitative urogenital ridge organ culture bioassay for MIS activity was used (Donahoe et al, 1976, 1977a,b,c; Meyers-Wallen et al, 1989), testes from affected neonates and embryos were found to have comparable MIS bioactivity during Müllerian duct regression as age-matched testes of normal dogs, confirming that the MIS was biologically functional. These findings indicated that target organ insensitivity caused by a mutation in either MISRII or a downstream gene in its signaling pathway was likely to be causative (Meyers-Wallen et al, 1993). In this study, we delineate the phenotype and clinical sequelae of this canine PMDS model in greater detail and identify the causative molecular defect in the pedigree with sex-limited autosomal recessive PMDS.
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Methods |
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Pedigree
The canine PMDS model pedigree was derived at the University of
Pennsylvania from 1 purebred miniature schnauzer litter containing 2 affected
males, as previously described
(Meyers-Wallen et al, 1989).
In experimental matings, 2 PMDS miniature schnauzer males from that initial
litter (A8 and A9, Figure 1)
were outcrossed to beagle females to produce F1 generations, which then
produced F2 and F1 backcross (F1BC) generations
(Meyers-Wallen et al, 1989).
Thereafter, the model was maintained by inbreeding within the pedigree. As
previously reported, 
2 analysis of affected dogs in the F2 and
F1BC generations excluded autosomal dominant inheritance of the trait
(P = .003). No PMDS males were produced when a proven carrier
miniature schnauzer female (A2) was bred to males of a different breed,
rejecting X-linked inheritance (P < .001, 2
analysis). However, sex-limited autosomal recessive inheritance, in which only
homozygous mutant males express the PMDS phenotype, could not be rejected
(F1BC, P = .92; F2, P = .53).
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Sequencing Canine PMDS MISRII
Canine MISRII is homologous to the human gene; therefore, the
exons (2, 3, 5, 6, 10) encoding the ligand binding and kinase domains that
have been reported to have a high frequency of mutations in human PMDS
patients were initially targeted for screening (Imbeaud et al,
1995,
1996;
Belville et al, 1999;
Messika-Zeitoun et al, 2001;
Hoshiya et al, 2003;
Zenteno et al, 2004;
Josso et al, 2005). Primer
pairs (Table 1) were
designed from the Canis familiaris chromosome 27 genomic contig,
containing whole genome sequence
(http://www.ncbi.nlm.nih.gov,
accession NW139903; range, 1800250–1806150), using Primer3
(http://frodo.wi.mit.edu).
Each primer pair was designed to amplify the entire exon and splice junctions
in the predicted C familiaris homolog of the human AMH receptor, type
II mRNA
(http://www.ncbi.nlm.nih.gov,
accession XM_543632) identified by the Basic Local Alignment Search Tool
(Altschul et al, 1990).
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Genomic DNA was extracted from stored whole blood samples of 38 dogs by standard phenol and chloroform extraction with ethanol precipitation (Sambrook et al, 1989) then quantified by spectrophotometry (NanoDrop ND-1000 spectrophotometer; NanoDrop Products, Wilmington, Delaware). Polymerase chain reaction (PCR) amplification of exons 2, 3, 5, 6, and 10 from genomic DNA was performed in the Mastercycler ep realplex PCR detection system (Eppendorf, Hamburg, Germany). Each PCR reaction (50 µl) contained 100–400 ng of DNA in reaction buffer with 1.5 mM MgCl2, 200 µM dNTPs, 200–300 nM of the primers, and Taq DNA polymerase (Roche Applied Science, Indianapolis, Indiana, or Denville Scientific INC, Metuchen, New Jersey). Reaction conditions were: initial denaturation (94°C, 5 minutes); then 30 cycles of denaturation (94°C, 20 seconds), annealing (50.6°C, 20 seconds), and extension (72°C, 30 seconds); with a final extension stage (72°C, 5 minutes).
PCR products were separated by electrophoresis in 1.5% agarose gels, and PCR-amplified products were purified with a MinElute Gel Extraction Kit (Qiagen, Valencia, California). The primer pairs (Table 1) were used for bidirectional sequencing with the Applied Biosystems BigDye V1.1 Cycle Sequencing Kit (Applied Biosystems 3130xl Genetic Analyzer; Applied Biosystems, Foster City, California; DNA Sequencing Facility, UMass Medical School) with the use of 15–25 ng of purified PCR products. The sequence output was processed with the FinchTV program (version l.4; Geospiza Inc, Seattle, Washington) and compared with the predicted mRNA sequence in the canine genome database (http://www.ncbi.nlm.nih.gov/blast).
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Results |
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TopAbstractMethodsResultsDiscussionReferences |
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Externally, PMDS dogs have a normal male phenotype, except that approximately 50% are either unilaterally or bilaterally cryptorchid (Meyers-Wallen et al, 1989). Late descent of the testis into the scrotum has been observed in some PMDS males of this model, for example A8 (Table 2). The cranial end of the uterine horn is firmly attached to the caudal pole of the testis, which can impair testis descent. Transverse testicular ectopia has not been identified in affected dogs of this model. Histological features of cryptorchid testes in PMDS dogs include absence of germ cells, whereas scrotal testes appear normal (Figures 3 and 4). Although PMDS males with bilateral scrotal testes were fertile, sperm counts were frequently lower than expected for body weight (Table 2). In 1 case, this was explained by unilateral segmental aplasia of the body of the epididymis (A8). The cause remains unknown in others, as no barrier to sperm transport was identified in the epididymis or vas deferens. Dogs with bilateral cryptorchidism were sterile. As in dogs that are not affected by PMDS but are unilaterally cryptorchid, PMDS males with unilateral cryptorchidism were subfertile, in that sperm counts were less than those of normal males of similar body weight (Table 2). However, by using timed breeding management, in which insemination was performed at the optimal period for fertilization, litters were obtained from all PMDS males with unilateral cryptorchidism that were bred (n = 3).
As in other cryptorchid dogs, Sertoli cell tumor (Figure 5) is a common sequela to cryptorchidism in aged PMDS males (Brown et al, 1976; Marshall et al, 1982). Pyometra is also reported in older PMDS miniature schnauzers (Marshall et al, 1982; Figure 5). A vaginal-urethral connection is the likely route for ascending infection in such cases. For example, at 14 months of age, a breeding PMDS male (A241; Table 2) developed pyometra, which was treated with a combination of systemic antibiotics and surgical therapy. Briefly, through a ventral approach into the prostatic urethra, the orifice of the vaginal-urethral connection was identified in the dorsal urethral wall, isolated by catheterization, and ligated. The uterine body was drained by marsupialization. Four weeks postoperatively, infection had resolved. Spermatozoa were not identified in monthly semen collections until 4 months postoperatively, after which the sperm count stabilized in the normal range. This male sired litters until retirement (4 years postoperatively; Table 2) and, to the authors' knowledge, is the only case of pyometra in a PMDS male dog in which fertility has been restored.
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Canine PMDS MISRII Sequence Analysis
The PCR-amplified sequences of canine MISRII exons 2, 5, 6, or 10
were identical among PMDS affected, unaffected, and heterozygous dogs. A
single base pair substitution (C241T) in exon 3 of the C familiaris
MISRII mRNA
(http://www.ncbi.nlm.nih.gov,
accession XM_543632) was identified (Figures
6 and
7). The nucleotide at this
position is cytosine in the predicted mRNA sequence from the canine genome
database and in unaffected dogs in this pedigree, as well as the unrelated
control beagle (Figure 1).
Homozygous thymidine substitution at this position alters the reading frame by
changing the codon from arginine to a stop codon (TGA) at nucleotides
241–243 in Exon 3 (Figure
7). Genotypes at the nucleotide 241 position are concordant with
the phenotypes of all dogs tested in the pedigree subset. Specifically, all
affected males are homozygous for the mutation (TT), and all males with a
normal phenotype are either wild type (CC) or heterozygous (CT)
(Figure 1). Furthermore, the
genotypes identified were consistent with the number of PMDS offspring
produced by individuals involved in experimental matings. For example, when
bred to PMDS males (TT), female A168 (TT) produced 9 PMDS males but no normal
males. Similarly, when bred to 2 proven carrier females, normal male A7 (CC)
produced 2 normal males but no PMDS males
(Figure 1;
Table 2). These results provide
the following genotypes at nucleotide 241 for the 38 dogs sequenced: 17 PMDS
males (TT), 11 phenotypically normal males (C/T or CC), 1 homozygous female
(TT), 8 heterozygous females (CT), and 1 homozygous normal female (CC).
Therefore these genotypes are not only concordant with the observed phenotypes
but are also consistent with sex-limited autosomal recessive inheritance of
the PMDS trait.
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Discussion |
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Because cryptorchidism was identified in only 50% of PMDS dogs in this pedigree, it is not a consistent finding in this canine model as it has been in humans. This raises the question of whether the human association of PMDS with cryptorchidism is due, in part, to ascertainment bias. Most human patients with PMDS are diagnosed coincidentally at the time of surgical procedures to correct undescended testis or transverse testicular ectopia (Brook et al, 1973; Sloan and Walsh, 1976). Milder phenotypes associated with retained Müllerian structures but descended, fertile testes and normal genitalia might remain undetected. The etiology of cryptorchidism associated with PMDS has been a matter of debate as to whether MIS plays a role in normal descent of the testis (Hutson, 2003) or whether the retained Müllerian structures physically compromise the ability of the testis to descend (Imbeaud et al, 1996). Imbeaud and colleagues noted that several patients with PMDS had a short vas deferens that is adherent or embedded within the uterine wall, which would physically prohibit testicular descent. Findings in the canine model support the latter hypothesis, as the lower pole of the testis remains physically attached to the cranial end of the uterine horn. In canine PMDS males with descended testes, the cranial uterine horn is drawn into the scrotum with the testis. Thus it is possible that the 50% of PMDS dogs with failure of testis descent result from the physical encumbrance of the uterus in inguinoscrotal descent.
Sequelae that occur in canine PMDS might provide some insight for human patients. Patients with persistent Müllerian remnants have been reported to develop urinary obstruction and urogenital tract infections (Tank and Hatch, 1986; Krstic et al, 2001; Lima et al, 2004), as well as gonadal tumors (Melman et al, 1981; Kazim, 1985; Snow et al, 1985). In addition to development of Sertoli cell tumors in cryptorchid testes, PMDS dogs can develop pyometra, as reported previously (Marshall et al, 1982). The vaginal-urethral connection between the cranial vagina and the prostatic urethra that we describe in PMDS dogs is of clinical significance. When present, this connection provides a route for ascending infection from the urethra to the uterus but is too narrow for adequate purulent outflow. Although routine treatment for canine pets with PMDS, with or without pyometra, is gonadectomy and hysterectomy, retention of fertility is of greater concern for human PMDS patients. Restoration of fertility subsequent to treatment for pyometra in the canine PMDS case described in this report indicates that sterility need not be a final outcome for human patients who develop secondary infection.
Canine PMDS MISRII Mutation
Molecular analysis of the MISRII gene in this canine pedigree
identified a C241T mutation in exon 3 of the MISRII gene that is the
genetic defect in PMDS miniature schnauzers. The genotype, normal (CC),
carrier (TC), or PMDS (TT) at this position is concordant with all phenotypes
in the pedigree subset and consistent with the sex-limited autosomal recessive
mode of inheritance. The mutation would cause premature termination of
translation at nucleotide 243; thus, the predicted protein product would
contain 80 amino acids instead of the normal 602. The truncated protein would
consist of a partial extracellular domain (exons 1–3) and lack the
entire transmembrane and intracellular signaling domains. As a result of this
mutation, we predict that the MISRII would be either rapidly degraded or
nonfunctional.
The canine MISRII gene is highly homologous to its human counterpart, AMHR2 (Imbeaud et al, 1995) and shares sequence similarity of approximately 30% with other TGF-beta type II receptors (Salhi et al, 2004). Human AMHR2 has 11 exons: the first 3 encode the signal sequence and extracellular domain, exon 4 encodes most of the transmembrane domain, and exons 5–11 encode the highly conserved intracellular serine-threonine kinase domains (Imbeaud et al, 1995). Mutations of human MISRII identified thus far have all been localized to exons encoding the extracellular ligand-binding domain or intracellular kinase domains (Imbeaud et al, 1995, 1996; Messika-Zeitoun et al, 2001; di Clemente and Belville, 2006). Human mutations in exon 3, similar to the one identified here in the canine PMDS model, lead to a stop codon, resulting in a truncated nonfunctional protein (Imbeaud et al, 1996). The most common human mutation, found in 25% of patients suspected to have a receptor defect, is a 27-bp deletion in exon 10, which deletes 9 amino acids from a critical kinase domain. Other reported mutations include deletions, splice mutations, and single base substitutions, causing nonsense and missense mutations. An in vitro system in which engineered constructs of human mutations are overexpressed in COS cells has been used to evaluate effects of mutations on ligand binding and downstream signaling (Messika-Zeitoun et al, 2001; Josso et al, 2005; di Clemente and Belville, 2006;).
We have identified the genetic mutation responsible for PMDS in the canine model derived from the miniature schnauzer. The genotypes at this newly discovered mutation site are consistent with the clinical phenotype of a large, carefully characterized pedigree, and with previous reports on the normal function of the MIS gene (Meyers-Wallen et al, 1989, 1993). In analogy to similar mutations reported in humans, the mutation predicts a nonfunctional truncated protein that would not be anchored in the cell membrane and has no kinase domain. Therefore, we conclude that the C241T mutation is not a nucleotide polymorphism, but rather, the causative genetic defect for PMDS in this canine model. Knowing the specific genetic defect responsible for PMDS in this pedigree should enable the development of a simple screening strategy to detect this mutation in other members of the miniature schnauzer breed. Identification of the genetic mutation in this canine model might also enable insights to be garnered from correlation of detailed clinical descriptions with molecular defects, which are difficult to study in the human condition.
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Acknowledgments |
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Footnotes |
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|| These authors contributed equally to this work. 
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