OMIA 000901-9615 : XX testicular DSD (Disorder of Sexual Development) in Canis lupus familiaris
SRY-negative XX sex reversal has now been reported in at least 28 breeds and mixed breeds, although not all were tested for SRY, as the PCR assay for canine SRY was not available prior to 1995 ([Meyers-Wallen et al., 1995a) . While this disorder may be genetically heterogeneous in the dog population in general, the mutation is likely to be identical by descent in closely related breeds, such as English and American cocker spaniels.
Normal mammalian prenatal sexual development depends upon the serial completion of three steps. The first is normal segregation of the sex chromosomes into the gametes, so that at fertilization, the zygote contains two sex chromosomes, either XX or XY. The second step is to translate chromosomal sex into gonadal sex, with XX individuals developing an ovary and XY individuals developing a testis. In mammals, gonadal sex is determined by genes on the autosomes and sex chromosomes. The third step is differentiation of the internal and external genitalia, which depends upon testicular hormones and their receptors and signaling pathways in target organs. Masculinization of the genitalia occurs in response to testis hormones, whereas female genitalia develop in their absence. Gonadal development begins with the emergence of the bipotential gonad. Shortly thereafter in XY embryos, a gene on the Y chromosome, SRY (sex determining region Y), dramatically upregulates an autosomal gene, SOX9 (SRY related HMG-box protein 9) during the critical period for Sertoli cell differentiation, which initiates testis development. Several other genes play a role in upregulating and maintaining SOX9 expression in the testis. In the ovarian pathway, R-spondin1 (RSPO1), a gene in the wingless-related protein family (WNT) signaling pathway, has a role in suppressing SOX9-mediated testis pathways in the developing ovary (reviewed in Jakob and Lovell-Badge, 2011). Both WNT4 and RSPO1 signaling lead to an increase in stabilized beta catenin. Recent evidence indicates that SOX9 and beta catenin act antagonistically (reviewed in Jakob and Lovell-Badge, 2011). Changes in gene expression in either the testis or ovarian pathway can disrupt gonadal development, leading to development of testes or ovotestes in XX individuals.
Molecular mechanisms reported for development of testes or ovotestes in XX individuals of other species include:
1) SOX9 upregulation during gonadal development induces testis development, either by duplication of SOX9 in XX humans (Huang et al 1999, Cox et al 2011, Vetro et al 2011) or by transgenic manipulation in XX mice (Bishop et al. 2000).
2) Mutations that eliminate or reduce RSPO1 expression. A null RSPO1 mutation induced testis development in related XX individuals (Parma et al. 2006), while a different RSPO1 mutation induced ovotestis development in another family (Tomaselli et al. 2008). Transgenic RSPO1 null mice develop ovotestes, not testes (Chassot et al. 2008).
3) SOX3 upregulation during gonadal development induces testis development, either by genomic rearrangement of its regulatory regions in XX humans, or transgenically in XX mice (Sutton et al. 2011).
4) Mutations that eliminate FOXL2 or PISRT1 expression induce testis development in XX polled goats (Pailhoux et al. 2001, Pannetier et al. 2005). This mechanism has not been identified as a cause of XX sex reversal in other species, and human FOXL2 mutations are associated with premature ovarian failure (De Baere et al. 2003).
The ACS model is strikingly similar to the subcategory of human XX DSD in which testes or ovotestes develop in 46,XX siblings, or within the same family, and the genetic defect is unknown [Skordis et al., 1987; Ostrer et al., 1989; Palmer et al., 1989; Kuhnle et al., 1993; Ramos et al., 1996; Slaney et al., 1998]. No candidate genes have yet been linked to the affected phenotype in dogs from the ACS research model (Kothapalli et al., 2003; Kothapalli et al., 2004; Kothapalli et al., 2005; Kothapalli et al., 2006; Pujar et al., 2005). ]. Exon scanning ruled out mutations in the coding region of canine RSPO1 in affected dogs of most breeds in which XX DSD has been reported [DeLorenzi et al., 2008].
Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT in 2001; updated by FN in 2015.Inheritance: The mode of inheritance in a large American cocker spaniel/Beagle model pedigree bred since 1982 specifically to study the genetics of this disorder was initially thought to be sex-limited autosomal recessive (Meyers-Wallen and Patterson, 1988), but more recent results from the same pedigree led Meyers-Wallen et al. (2017) to conclude "that simple Mendelian inheritance alone was insufficient to account for XX DSD expression" in this pedigree. Both XX males and XX true hermaphrodites can occur within the same litter or pedigree. The disorder in the ACS is very similar to the form of human XX DSD where testicular DSD and ovotesticular DSD occur in siblings or within the larger family (Meyers-Wallen, 2011). The mode of inheritance is not established for the other dog breeds in which this trait has been identified. The causative mutation in all breeds is unknown. In breeds that are closely related, the disorder is likely to be caused by the same mutation, and therefore have the same mode of inheritance. In unrelated breeds this disorder may be genetically heterogeneous (Meyers-Wallen et al., 1999). Mapping: A genome-wide linkage screen localized the sex-reversal locus to a 5.4-Mb region on CFA29 in a study on affected American Cocker Spaniels (Pujar et al., 2007). As reported by Meyers-Wallen et al. (2017), "We now consider the CFA29 linkage to be a false positive result due to CanFam1 assembly errors."
A Robertsonian translocation involving CFA23 was identified in one affected Bernese mountain dog (Switonski et al., 2011).
A GWAS involving 23 dogs from the model pedigree plus 4 Beagle controls, each genotyped with the Affymetrix version 2 canine SNP array, enabled Meyers-Wallen et al. (2017) to map the disorder to a 4.27MB region of CFA9 that "overlaps the canine ortholog for the upstream regulatory region of human SOX9" but "does not include the canine SOX9 coding region". Whole-genome sequencing narrowed the candidate region to 1.9MB containing 244 SNPs.Markers: In their 1.9MB candidate region, Meyers-Wallen et al. (2017) "identified a variant on C. familiaris autosome 9 (CFA9) ["a guanine insertion (G+) at CFA9: 6048201–6048202 . . . , rs852549625)"] that is associated with XX DSD in the canine model and in affected purebred dogs". This variant is, in effect, a marker for what is now regarded as a multifactorial trait. Interestingly, Meyers-Wallen et al. (2017) showed that homozygosity for this variant "is associated with embryonic lethality in at least one breed" (German shorthaired pointer). Molecular basis: Rossi et al. (2014) reported a duplication of a 577kb region on chromosome CFA9 (from 11,016,965 to 11,593,933; CanFam2 genome assembly) containing SOX9, a gene with a central involvement in sex determination, in 2 of 7 cases of this disorder. From a larger study involving 16 affected and 30 control dogs, Marcinkowska-Swojak et al. (2015) concluded that "Our extensive studies have excluded duplication of SOX9 as the common cause of XX DSD in analyzed samples". Szczerbal et al. (2016) reported a single affected dog heterozygous for a de novo large variant in "the CNV region (CNVR) upstream of the SOX9 gene". Taken together, these three results do not appear to strongly implicate CNV in the region of the SOX9 gene as being causative of this disorder. This conclusion was confirmed by Meyers-Wallen et al. (2017) who explain that "none of . . . [the above variants] has been confirmed as a cause of inherited XX DSD". These same authors reported a new variant upstream of the SOX9 gene as being associated with XX DSD. In concluding that their study "of this variant indicates that XX DSD is a complex trait in which breed genetic background affects penetrance", these authors are, in effect, saying that this traits is multifactorial, and that a likely causal variant of large effect has yet to be discovered.
Consistent with this conclusion, Nowacka-Woszuk et al. (2019) "showed that CNVR1, located upstream of SOX9, is associated with the XX DSD phenotype, though in a breed-specific manner. Duplication of the SOX9 gene is a rare cause of this disorder in dogs. Moreover, we did not observe any association of G-insertion with the DSD phenotype. We assume that the genetic background of XX DSD can be different in certain breeds."Clinical features: Affected dogs (XX male, testicular XX DSD) are most appear as bilaterally cryptorchid male dogs, but have a caudally displaced and pendulous prepuce and hypoplastic penis. Mild hypospadias may also be present. These dogs are sterile (Meyers-Wallen et al., 1988). Variable degrees of masculinization are found in affected dogs with ovotestes (XX true hermaphrodite, ovotesticular DSD). Those most masculinized have an enlarged clitoris containing a bone and/or a misshapen vulva that resembles a prepuce. Clitoral enlargement may be noted within a few months of age or at puberty. Many XX true hermaphrodites in the ACS studies had an apparently normal female external phenotype (Meyers-Wallen and Patterson 1988). Affected dogs with ovotestes may exhibit estrous cycles and rarely, produce offspring.
Both XX males and XX true hermaphrodites can occur within the same litter or in the same pedigree.Pathology: A spectrum of phenotypic variation correlated to the amount of testicular tissue present in the individual was identified in studies of affected ACS dogs (Meyers-Wallen et al., 1988), as follows:
1) XX males with bilateral testes had bilateral epididymides, a prostate, Wolffian duct derivatives, and a complete uterus. The external genitalia included a caudally displaced and pendulous prepuce, hypoplastic penis and usually bilateral cryptorchidism .
2) True hermaphrodites with unilateral or bilateral ovotestes had oviducts and/or epididymides, and a complete uterus. Externally, an enlarged clitoris with a bone and/or misshapen vulva resembling a prepuce, was present in some. In others, the external genitalia had a female phenotype
3) True hermaphrodites with one ovotestis had bilateral oviducts, a complete uterus, and normal female external genitalia.
Although biologically active Müllerian inhibiting substance (MIS) is present in neonatal testes and ovotestes from affected dogs, the timing of MIS secretion is delayed. This could explain why the cranial Müllerian ducts regress but the uterus remains (Meyers-Wallen, 2011).Prevalence: SRY-negative XX sex reversal has been identified in at least 28 dog breeds and a mixed breed dog. Control: While XX males are sterile, some XX true hermaphrodites have exhibited estrous cycles and reproduced as females.
To prevent production of affected dogs, breeding of true hermaphrodites or proven carriers (i.e., parents of affected dogs) should be avoided.Genetic testing: Diagnosis is dependent upon karyotype (78,XX), PCR assay confirming that SRY is absent in genomic DNA, and histology confirming the presence of testicular tissue in one or both gonads (ovotestes or testes). Breeds: Afghan Hound, American Cocker Spaniel, American Pit Bull Terrier, American Staffordshire Terrier, Australian Shepherd, Basset Hound, Beagle, Bernese Mountain dog, Border Collie, Brussels Griffon, Bull Terrier, Bulldog, Doberman Pinscher, English Cocker Spaniel, French Bulldog, German Pinscher, German Shepherd Dog, German Shorthaired Pointer, Golden Retriever, Jack Russell Terrier, Kerry Blue Terrier, Norwegian Elkhound, Podenco, Pug, Soft Coated Wheaten Terrier, Tibetan Terrier, Vizsla, Walker Hound, Weimaraner, wheaten terrier.
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2021||Walter, B., Flock, U., Leykam, C., Otzdorff, C., Simmet, K., Hecht, W., Kempker, L., Aupperle-Lellbach, H., Reese, S. :|
|Serum anti-Müllerian hormone concentration as a diagnostic tool to identify testicular tissue in canine disorders of sexual development. Domest Anim Endocrinol 78:106654, 2021. Pubmed reference: 34509739. DOI: 10.1016/j.domaniend.2021.106654.|
|2020||Szczerbal, I., Nowacka-Woszuk, J., Nizanski, W., Dzimira, S., Ligocka, Z., Jastrzebska, A., Kabala, B., Biernacik, M., Przadka, P., Switonski, M. :|
|Disorders of Sex Development Are an Emerging Problem in French Bulldogs: A Description of Six New Cases and a Review of the Literature. Sex Dev :, 2020. Pubmed reference: 32203972. DOI: 10.1159/000506582.|
|2019||Nowacka-Woszuk, J., Szczerbal, I., Stachowiak, M., Szydlowski, M., Nizanski, W., Dzimira, S., Maslak, A., Payan-Carreira, R., Wydooghe, E., Nowak, T., Switonski, M. :|
|Association between polymorphisms in the SOX9 region and canine disorder of sex development (78,XX; SRY-negative) revisited in a multibreed case-control study. PLoS One 14:e0218565, 2019. Pubmed reference: 31220175. DOI: 10.1371/journal.pone.0218565.|
|2018||Yoon, H., Han, S.H., Kim, J., Kim, K., Eom, K. :|
|Urogenital anomalies and urinary incontinence in an English Cocker Spaniel dog with XX sex reversal. J Vet Intern Med :, 2018. Pubmed reference: 29572943. DOI: 10.1111/jvim.15119.|
|2017||Meyers-Wallen, V.N., Boyko, A.R., Danko, C.G., Grenier, J.K., Mezey, J.G., Hayward, J.J., Shannon, L.M., Gao, C., Shafquat, A., Rice, E.J., Pujar, S., Eggers, S., Ohnesorg, T., Sinclair, A.H. :|
|XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). PLoS One 12:e0186331, 2017. Pubmed reference: 29053721. DOI: 10.1371/journal.pone.0186331.|
|2016||Szczerbal, I., Nowacka-Woszuk, J., Dzimira, S., Atamaniuk, W., Nizanski, W., Switonski, M. :|
|A Rare Case of Testicular Disorder of Sex Development in a Dog (78,XX; SRY-Negative) with Male External Genitalia and Detection of Copy Number Variation in the Region Upstream of the SOX9 Gene. Sex Dev 10:74-8, 2016. Pubmed reference: 27089505. DOI: 10.1159/000445464.|
|2015||Marcinkowska-Swojak, M., Szczerbal, I., Pausch, H., Nowacka-Woszuk, J., Flisikowski, K., Dzimira, S., Nizanski, W., Payan-Carreira, R., Fries, R., Kozlowski, P., Switonski, M. :|
|Copy number variation in the region harboring SOX9 gene in dogs with testicular/ovotesticular disorder of sex development (78,XX; SRY-negative). Sci Rep 5:14696, 2015. Pubmed reference: 26423656. DOI: 10.1038/srep14696.|
|2014||Rossi, E., Radi, O., De Lorenzi, L., Vetro, A., Groppetti, D., Bigliardi, E., Luvoni, G.C., Rota, A., Camerino, G., Zuffardi, O., Parma, P. :|
|Sox9 duplications are a relevant cause of Sry-negative XX sex reversal dogs. PLoS One 9:e101244, 2014. Pubmed reference: 25010117. DOI: 10.1371/journal.pone.0101244.|
|Salamon, S., Nowacka-Woszuk, J., Szczerbal, I., Dzimira, S., Nizanski, W., Ochota, M., Switonski, M. :|
|A lack of association between polymorphisms of three positional candidate genes (CLASP2 , UBP1, and FBXL2) and canine disorder of sexual development (78,XX; SRY -negative). Sex Dev 8:160-5, 2014. Pubmed reference: 24994500. DOI: 10.1159/000363531.|
|2012||Groppetti, D., Genualdo, V., Bosi, G., Pecile, A., Iannuzzi, A., Perucatti, A., De Lorenzi, L., Parma, P., Arrighi, S. :|
|XX SRY-negative true hermaphrodism in two dogs: clinical, morphological, genetic and cytogenetic studies. Sex Dev 6:135-42, 2012. Pubmed reference: 21921586. DOI: 10.1159/000331274.|
|Max, A., Grabiec, A., Sacharczuk, M., Sysa, P., Jurka, P., Krzyżewska, A. :|
|78,XX testicular DSD syndrome in a mongrel dog. Reprod Domest Anim 47:e7-e11, 2012. Pubmed reference: 21762213. DOI: 10.1111/j.1439-0531.2011.01834.x.|
|Meyers-Wallen, V.N. :|
|Gonadal and sex differentiation abnormalities of dogs and cats. Sex Dev 6:46-60, 2012. Pubmed reference: 22005097. DOI: 10.1159/000332740.|
|Switonski, M., Payan-Carreira, R., Bartz, M., Nowacka-Woszuk, J., Szczerbal, I., Colaço, B., Pires, M.A., Ochota, M., Nizanski, W. :|
|Hypospadias in a male (78,XY; SRY-positive) dog and sex reversal female (78,XX; SRY-negative) dogs: clinical, histological and genetic studies. Sex Dev 6:128-34, 2012. Pubmed reference: 21893969. DOI: 10.1159/000330921.|
|2011||Campos, M., Moreno-Manzano, V., García-Roselló, M., García-Roselló, E. :|
|Sry-negative XX sex reversal in a French Bulldog. Reprod Domest Anim 46:185-8, 2011. Pubmed reference: 20412513. DOI: 10.1111/j.1439-0531.2010.01612.x.|
|Switonski, M., Szczerbal, I., Nizanski, W., Kociucka, B., Bartz, M., Dzimira, S., Mikolajewska, N. :|
|Robertsonian translocation in a sex reversal dog (XX, SRY negative) may indicate that the causative mutation for this intersexuality syndrome resides on canine chromosome 23 (CFA23). Sex Dev 5:141-6, 2011. Pubmed reference: 21430365. DOI: 10.1159/000324689.|
|2010||Rota, A., Cucuzza, A.S., Iussich, S., Delorenzi, L., Parma, P. :|
|The case of an Sry-negative XX male Pug with an inguinal gonad. Reprod Domest Anim 45:743-5, 2010. Pubmed reference: 19210664. DOI: 10.1111/j.1439-0531.2008.01335.x.|
|2009||Buijtels, J.J., de Gier, J., van Haeften, T., Kooistra, H.S., Spee, B., Veldhuis Kroeze, E.J., Zijlstra, C., Okkens, A.C. :|
|Minimal external masculinization in a SRY-negative XX male Podenco dog. Reprod Domest Anim 44:751-6, 2009. Pubmed reference: 18992091. DOI: 10.1111/j.1439-0531.2008.01065.x.|
|2008||De Lorenzi, L., Groppetti, D., Arrighi, S., Pujar, S., Nicoloso, L., Molteni, L., Pecile, A., Cremonesi, F., Parma, P., Meyers-Wallen, V. :|
|Mutations in the RSPO1 coding region are not the main cause of canine SRY-negative XX sex reversal in several breeds. Sex Dev 2:84-95, 2008. Pubmed reference: 18577875. DOI: 10.1159/000129693.|
|2007||Pujar, S., Kothapalli, K.S., Göring, H.H., Meyers-Wallen, V.N. :|
|Linkage to CFA29 detected in a genome-wide linkage screen of a canine pedigree segregating Sry-negative XX sex reversal. J Hered 98:438-44, 2007. Pubmed reference: 17591608. DOI: 10.1093/jhered/esm028.|
|2006||Kothapalli, K.S., Kirkness, E.F., Vanwormer, R., Meyers-Wallen, V.N. :|
|Exclusion of DMRT1 as a candidate gene for canine SRY-negative XX sex reversal. Vet J 171:559-61, 2006. Pubmed reference: 16624726. DOI: 10.1016/j.tvjl.2004.12.013.|
|2005||Kothapalli, K., Kirkness, E., Pujar, S., Van Wormer, R., Meyers-Wallen, V.N. :|
|Exclusion of candidate genes for canine SRY-negative XX sex reversal. J Hered 96:759-63, 2005. Pubmed reference: 16267164. DOI: 10.1093/jhered/esi129.|
|Kuiper, H., Bunck, C., Gunzel-Apel, AR., Drogemuller, C., Hewicker-Trautwein, M., Distl, O. :|
|SRY-negative XX sex reversal in a Jack Russell Terrier: a case report. Vet J 169:116-7, 2005. Pubmed reference: 15683773. DOI: 10.1016/j.tvjl.2003.11.004.|
|Nowacka, J., Nizanski, W., Klimowicz, M., Dzimira, S., Switonski, M. :|
|Lack of the SOX9 gene polymorphism in sex reversal dogs (78,XX; SRY negative). J Hered 96:797-802, 2005. Pubmed reference: 16150950. DOI: 10.1093/jhered/esi106.|
|Pujar, S., Kothapalli, K.S., Kirkness, E., Van Wormer, R.H., Meyers-Wallen, V.N. :|
|Exclusion of Lhx9 as a candidate gene for Sry-negative XX sex reversal in the American cocker spaniel model. J Hered 96:452-4, 2005. Pubmed reference: 15814894. DOI: 10.1093/jhered/esi058.|
|2004||Kothapalli, KS., Kirkness, EF., Pujar, S., Meyers-Wallen, VN. :|
|Exclusion of WT1 as a candidate gene for canine SRY-negative XX sex reversal. Anim Genet 35:466-7, 2004. Pubmed reference: 15566472. DOI: 10.1111/j.1365-2052.2004.01189.x.|
|2003||Kothapalli, KS., Kirkness, E., Natale, LJ., Meyers-Wallen, VN. :|
|Exclusion of PISRT1 as a candidate locus for canine Sry-negative XX sex reversal. Anim Genet 34:467-9, 2003. Pubmed reference: 14687082.|
|1999||Hubler, M., Hauser, B., Meyers-Wallen, V.N., Arnold, S. :|
|Sry-negative XX true hermaphrodite in a Basset hound. Theriogenology 51:1391-403, 1999. Pubmed reference: 10729102. DOI: 10.1016/S0093-691X(99)00082-5.|
|Melniczek, J.R., Dambach, D., Prociuk, U., Jezyk, P.F., Henthorn, P.S., Patterson, D.E., Giger, U. :|
|SRY-negative XX sex reversal in a family of Norwegian Elkhounds Journal of Veterinary Internal Medicine 13:564-569, 1999. Pubmed reference: 10587257.|
|Meyers-Wallen, V.N., Schlafer, D., Barr, I., Lovell-Badge, R., Keyzner, A. :|
|Sry-negative XX sex reversal in purebred dogs Molecular Reproduction & Development 53:266-273, 1999.|
|Meyers-Wallen, V.N. :|
|Inherited disorders in sexual development Journal of Heredity 90:93-95, 1999. Pubmed reference: 9987911.|
|1997||Williams, J., Partington, B.P., Smith, B., Hedlund, C.S., Law, J.M. :|
|Pyovagina and stump pyometra in a neutered XX sex-reversed Beagle - a case report Journal of the American Animal Hospital Association 33:83-90, 1997. Pubmed reference: 8974032.|
|1995||Meyers-Wallen, V.N., Palmer, V.L., Acland, G.M., Hershfield, B. :|
|SRY-negative XX sex reversal in the American Cocker Spaniel dog Molecular Reproduction and Development 41:300-305, 1995. Pubmed reference: 8588928. DOI: 10.1002/mrd.1080410304.|
|Meyers-Wallen, V.N., Bowman, L., Acland, G.M., Palmer, V.L., Schlafer, D., Fajt, V. :|
|SRY-negative XX sex reversal in the German Shorthaired Pointer dog Journal of Heredity 86:369-374, 1995. Pubmed reference: 7560873.|
|1994||Meyers-Wallen, V.N., Maclaughlin, D., Palmer, V., Donahoe, P.K. :|
|Mullerian-inhibiting substance secretion is delayed in XX sex- reversed dog embryos Molecular Reproduction and Development 39:1-7, 1994. Pubmed reference: 7999353. DOI: 10.1002/mrd.1080390102.|
|1993||Meyers-Wallen, V.N. :|
|Genetics of sexual differentiation and anomalies in dogs and cats. Journal of Reproduction and Fertility :441-452, 1993. Pubmed reference: 8229960.|
|1988||Meyers-Wallen, V.N., Patterson, D.F. :|
|XX sex reversal in the American cocker spaniel dog: phenotypic expression and inheritance Human Genetics 80:23-30, 1988. Pubmed reference: 3417302.|
|1987||Meyers-Wallen, V.N., Donahoe, P.K., Manganaro, T., Patterson, D.F. :|
|Mullerian inhibiting substance in sex-reversed dogs Biology of Reproduction 37:1015-1022, 1987. Pubmed reference: 3689844.|
|1984||Selden, J.R., Moorhead, P.S., Koo, G.C., Wachtel, S.S., Haskins, M.E., Patterson, D.F. :|
|Inherited XX sex reversal in the cocker spaniel dog. Hum Genet 67:62-9, 1984. Pubmed reference: 6745927.|
|1978||Selden, J.R., Wachtel, S.S., Koo, G.C., Haskins, M.E., Patterson, D.F. :|
|Genetic basis of XX male syndrome and XX true hermaphroditism: evidence in the dog. Science 201:644-6, 1978. Pubmed reference: 675252.|
- Created by Frank Nicholas on 18 Sep 2005
- Changed by Vicki Meyers-Wallen on 11 Aug 2011
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