OMIA 001335-9615 : Renal cystadenocarcinoma and nodular dermatofibrosis in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 135150

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".

Breed: German Shepherd Dog.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
FLCN folliculin Canis lupus familiaris 5 NC_006587.3 (42176093..42195718) FLCN Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
German Shepherd Dog Renal cystadenocarcinoma and nodular dermatofibrosis FLCN missense CanFam3.1 5 g.42186445A>G c.764A>G p.H255R 2003 14532326 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


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.
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.

Edit History


  • Created by Frank Nicholas on 02 Nov 2010
  • Changed by Frank Nicholas on 28 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 21 Sep 2012
  • Changed by Frank Nicholas on 22 Nov 2013
  • Changed by Tosso Leeb on 23 Dec 2015