This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For this new project in 2006, we have recently obtained part of the breeding colony of XX sex reversal dogs from Dr. Vicki Meyers-Wallen at Cornell Universtiy. In XX sex reversal, affected individuals have a normal female karyotype (46,XX), and no Y chromosome, yet develop testicular tissue in the gonad. Affected individuals develop testes (XX male) or ovotestes (XX true hermaphrodite). Some XX males have a Y to autosome translocation containing the testis determining gene SRY. However, in SRY-negative XX sex reversal, affected individuals have no Y chromosome and no SRY gene. The frequency of XX males is approximately 1 in 20,000 human births with 10-20% being SRY-negative. The cause of testis induction in the majority of these patients remains unexplained, as a specific genetic defect in XX males has been identified in only one sporadic case and one family with linked cutaneous disease. Additionally, XX true hermaphrodites, which develop ovotestes, occur as siblings of XX males in some families and also within families in which XX males are absent. The mechanism of testis induction in these individuals remains unknown. Characterization of the molecular basis for this disorder would increase our understanding of testis induction and provide diagnostic tests for sex determination disorders. It is difficult to identify such genes in humans since the disorders are uncommon, family sizes are small, and the likelihood of genetic heterogeneity is large. Animal models lack these disadvantages. The canine pedigree segregating the sex reversal trait is strikingly similar to familial SRY-negative XXSR in which XX males and XX true hermaphrodites occur as full siblings. As in humans, canine XX males develop bilateral testes and XX true hermaphrodites develop bilateral ovotestes. Both have a normal female karyotype (78,XX) and Sry is absent, as assayed by Southern blot with a full-length canine Sry probe and polymerase chain reaction with canine specific Sry primers. The causative gene is unknown, but a linked 2 Mb region has been identified in the canine pedigree segregating this trait, using linkage disequilibrium analysis and fine mapping with microsatellite markers. Results to date support a novel etiologic gene as causative in this model, and candidate genes are under investigation. The canine model has several advantages over other animal models. Transgenic mice have been useful to study known genes, but the lack of naturally-occurring mouse models of Sry-negative XXSR suggests that the mouse may not be the model of choice for this particular disorder. Gene expression in normal canine embryonic gonads is similar to that of humans and domestic animals in temporal and spatial expression of key genes involved in sex determination, unlike the mouse. Thus, the canine model is a representative model of mammalian sex determination and has an advantage over other domesticated animals in that it can produce multiple embryos per litter. Furthermore, canine molecular tools (7x canine genome sequence, SNP map) are available to assist positional cloning and to define gene expression patterns during embryonic gonadal sex determination. Thus, the canine model of this disorder is an important model for novel gene discovery and documentation of the molecular mechanism of their role in mammalian sex determination. --

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Material Resource Grants (P40)
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National Center for Research Resources Initial Review Group (RIRG)
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University of Pennsylvania
Schools of Veterinary Medicine
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Lok, J B; Shao, H; Massey, H C et al. (2017) Transgenesis in Strongyloides and related parasitic nematodes: historical perspectives, current functional genomic applications and progress towards gene disruption and editing. Parasitology 144:327-342
Casal, Margret L; Wang, Ping; Mauldin, Elizabeth A et al. (2017) A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs. PLoS One 12:e0170708
Mauldin, Elizabeth A; Wang, Ping; Olivry, Thierry et al. (2017) Epidermolysis bullosa simplex in sibling Eurasier dogs is caused by a PLEC non-sense variant. Vet Dermatol 28:10-e3
Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter et al. (2016) Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII. Mol Ther 24:206-216
Nicoli, Elena-Raluca; Al Eisa, Nada; Cluzeau, Celine V M et al. (2016) Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease. PLoS One 11:e0152007
Hunt, Vicky L; Tsai, Isheng J; Coghlan, Avril et al. (2016) The genomic basis of parasitism in the Strongyloides clade of nematodes. Nat Genet 48:299-307
Mohandas, Namitha; Hu, Min; Stroehlein, Andreas J et al. (2016) Reconstruction of the insulin-like signalling pathway of Haemonchus contortus. Parasit Vectors 9:64
Tritschler, Claudia; Mizukami, Keijiro; Raj, Karthik et al. (2016) Increased erythrocytic osmotic fragility in anemic domestic shorthair and purebred cats. J Feline Med Surg 18:462-70
Flanagan-Steet, Heather; Aarnio, Megan; Kwan, Brian et al. (2016) Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting. J Bone Miner Res 31:535-48
Albarqi, Mennatallah M Y; Stoltzfus, Jonathan D; Pilgrim, Adeiye A et al. (2016) Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid. PLoS Pathog 12:e1005358

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