OMIA:001335-9615 : Renal cystadenocarcinoma and nodular dermatofibrosis in Canis lupus familiaris
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 135150 (trait) , 607273 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal dominant
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2003
Species-specific name: Renal cancer syndrome
Species-specific symbol: RCND
Inheritance: A pedigree analysis by Lium and Moe (1985) implicated autosomal dominant inheritance, which was confirmed by Moe et al. (1998).
Mapping: Using a genome scan with mapped microsatellites, Jónasdóttir et al. (2000) mapped the RCND locus to "a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (θ) of 0.016, supported by a logarithm of odds score of 16.7". To the authors' knowledge, this was "the first localization of a mammalian cancer syndrome to be mapped in a species other than human and rat".
Molecular basis: The causal mutation was discovered via a comparative positional cloning approach. Building on the mapping results described in the Mapping section above, Lingaas et al. (2003) narrowed the candidate region homologous to human HSA17p, which includes the BHD gene, mutations in which cause Birt–Hogg–Dubé syndrome, which is very similar to the canine disorder. Sequencing of the canine BHD gene showed that this disorder in German Shepherd dogs is due to an A>G base substitution in exon 7 of the BHD (folliculin) gene, leading to a H255R amino-acid substitution in a highly conserved region. Using genetic variant nomenclature as of 2015, the causative variant would be denoted as c.764A>G or p.His255Arg.
Clinical features: As summarised by Lingaas et al. (2003), "The disease is characterized by bilateral, multifocal tumors in the kidneys, uterine leiomyomas and nodules in the skin consisting of dense collagen fibers".
Ciccarelli et al. (2019) reported a case of "Unilateral renal cystadenocarcinoma and nodular dermatofibrosis in a mixed-breed dog carrying . . . [the p.His255Arg] FLCN gene mutation", concluding that "This case supports the hypothesis that nodular dermatofibrosis is not a paraneoplastic syndrome associated with cystadenocarcinoma. It may be instead an independent dermatological feature of the same genetic disease, linked to the mutation of FLCN given that the cutaneous nodules in this dog increased in size and number after removal of the adenocarcinoma."
Breed: German Shepherd Dog.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|FLCN||folliculin||Canis lupus familiaris||5||NC_051809.1 (42284487..42304049)||FLCN||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|77||German Shepherd Dog||Renal cystadenocarcinoma and nodular dermatofibrosis||FLCN||missense||Naturally occurring variant||CanFam3.1||5||g.42186445A>G||c.764A>G||p.(H255R)||rs1152388411||rs1152388411||2003||14532326||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
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.
|2019||Ciccarelli, S., Di Bello, A., Valastro, C., Leo, C., Lenoci, D., Rana, E., Franchini, D. :|
|Unilateral renal cystadenocarcinoma and nodular dermatofibrosis in a mixed-breed dog carrying a FLCN gene mutation. Vet Dermatol :, 2019. Pubmed reference: 30672048 . DOI: 10.1111/vde.12719.|
|2013||Zanatta, M., Bettini, G., Scarpa, F., Fiorelli, F., Rubini, G., Mininni, A.N., Capitani, O. :|
|Nodular dermatofibrosis in a dog without a renal tumour or a mutation in the folliculin gene. J Comp Pathol 148:248-51, 2013. Pubmed reference: 22871425 . DOI: 10.1016/j.jcpa.2012.06.010.|
|2009||Bønsdorff, T.B., Jansen, J.H., Thomassen, R.F., Lingaas, F. :|
|Loss of heterozygosity at the FLCN locus in early renal cystic lesions in dogs with renal cystadenocarcinoma and nodular dermatofibrosis. Mamm Genome 20:315-20, 2009. Pubmed reference: 19387735 . DOI: 10.1007/s00335-009-9183-8.|
|2008||Bønsdorff, T.B., Jansen, J.H., Lingaas, F. :|
|Second hits in the FLCN gene in a hereditary renal cancer syndrome in dogs. Mamm Genome 19:121-6, 2008. Pubmed reference: 18219524 . DOI: 10.1007/s00335-007-9088-3.|
|Gardiner, D.W., Spraker, T.R. :|
|Generalized nodular dermatofibrosis in the absence of renal neoplasia in an Australian Cattle Dog. Vet Pathol 45:901-4, 2008. Pubmed reference: 18984793 . DOI: 10.1354/vp.45-6-901.|
|2004||Comstock, K.E., Lingaas, F., Kirkness, E.F., Hitte, C., Thomas, R., Breen, M., Galibert, F., Ostrander, E.A. :|
|A high-resolution comparative map of canine Chromosome 5q14.3-q33 constructed utilizing the 1.5x canine genome sequence. Mamm Genome 15:544-51, 2004. Pubmed reference: 15366374 .|
|2003||Lingaas, F., Comstock, K.E., Kirkness, E.F., Sørensen, A., Aarskaug, T., Hitte, C., Nickerson, M.L., Moe, L., Schmidt, L.S., Thomas, R., Breen, M., Galibert, F., Zbar, B., Ostrander, E.A. :|
|A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum Mol Genet 12:3043-53, 2003. Pubmed reference: 14532326 . DOI: 10.1093/hmg/ddg336.|
|Vercelli, A., Bellone, G., Abate, O., Emanuelli, G., Cagnasso, A. :|
|Expression of transforming growth factor-beta isoforms in the skin, kidney, pancreas and bladder in a German shepherd dog affected by renal cystadenocarcinoma and nodular dermatofibrosis. J Vet Med A Physiol Pathol Clin Med 50:506-10, 2003. Pubmed reference: 15157018 .|
|2000||Jonasdottir, T.J., Mellersh, C.S., Moe, L., Heggebo, R., Gamlem, H., Ostrander, E.A., Lingaas, F. :|
|Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs Proceedings of the National Academy of Sciences of the United States of America 97:4132-4137, 2000. Pubmed reference: 10759551 . DOI: 10.1073/pnas.070053397.|
|Moe, L., Gamlem, H., Jónasdóttir, T.J., Lingaas, F. :|
|Renal microcystic tubular lesions in two 1Year-old dogs - an early sign of hereditary renal cystadenocarcinoma? J Comp Pathol 123:218-21, 2000. Pubmed reference: 11032680 . DOI: 10.1053/jcpa.2000.0408.|
|1998||Moe, L. , Norwegian School of Veterinary Science (eds) :|
|Norwegian School of Veterinary Science Publications, 1997. Bibliotekets Arsmelding, Oslo :1-24, 1998.|
|1997||Moe, L., Lium, B. :|
|Computed tomography of hereditary multifocal renal cystadenocarcinomas in German Shepherd dogs Veterinary Radiology & Ultrasound 38:335-343, 1997. Pubmed reference: 9335089 .|
|Moe, L., Lium, B. :|
|Hereditary multifocal renal cystadenocarcinomas and nodular dermatofibrosis in 51 German Shepherd dogs Journal of Small Animal Practice 38:498-505, 1997. Pubmed reference: 9403809 .|
|1986||Cosenza, S.F., Seely, J.C. :|
|Generalized nodular dermatofibrosis and renal cystadenocarcinomas in a German shepherd dog. J Am Vet Med Assoc 189:1587-90, 1986. Pubmed reference: 3793598 .|
|1985||Lium, B, Moe, L. :|
|Hereditary multifocal renal cystadenocarcinomas and nodular dermatofibrosis in the German Shepherd dog: macroscopic and histopathologic changes Veterinary Pathology 22:447-455, 1985. Pubmed reference: 4049673 .|
|1984||Moe, L., Lium, B. :|
|Multiple bilateral renal cystadenocarcinomas in the German Shepherd dog. A case emphasizing the use of radiographic examination [Norwegian] Norsk Veterinaertidsskrift 96:687-692, 1984.|
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