An Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs
Leonberger dogs are a breed originally produced by crossing large-bodied dogs, including Saint Bernards and Newfoundlands. A peripheral neuropathy has been described in Leonbergers that is similar to a group of inherited polyneuropathies known as Charcot-Marie-Tooth disease in humans. We collected a cohort of well-characterized Leonberger polyneuropathy cases and controls, conducted a genome-wide association study, and ultimately identified a highly associated and likely causative mutation in the AHGEF10 gene. This sequence variant is a 10-bp deletion encompassing a splice site, which forces use of a downstream splice site to create a processed mRNA with a premature stop codon, and represents a loss-of-function mutation. The identical mutation was also found in several polyneuropathy-affected Saint Bernards. When homozygous, this deletion results in the onset of clinical signs before four years of age. ARHGEF10 has not previously been associated with severe CMT, but comes from a family of genes shown to be involved in neuron morphology. This first-documented severe polyneuropathy associated with an ARHGEF10 mutation in any species provides an opportunity to gain further insights into the pathobiology of diseases associated with this gene. The ARHGEF10 mutation does not, however, by itself account for all cases of polyneuropathy in Leonbergers or Saint Bernards.
Vyšlo v časopise:
An Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004635
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004635
Souhrn
Leonberger dogs are a breed originally produced by crossing large-bodied dogs, including Saint Bernards and Newfoundlands. A peripheral neuropathy has been described in Leonbergers that is similar to a group of inherited polyneuropathies known as Charcot-Marie-Tooth disease in humans. We collected a cohort of well-characterized Leonberger polyneuropathy cases and controls, conducted a genome-wide association study, and ultimately identified a highly associated and likely causative mutation in the AHGEF10 gene. This sequence variant is a 10-bp deletion encompassing a splice site, which forces use of a downstream splice site to create a processed mRNA with a premature stop codon, and represents a loss-of-function mutation. The identical mutation was also found in several polyneuropathy-affected Saint Bernards. When homozygous, this deletion results in the onset of clinical signs before four years of age. ARHGEF10 has not previously been associated with severe CMT, but comes from a family of genes shown to be involved in neuron morphology. This first-documented severe polyneuropathy associated with an ARHGEF10 mutation in any species provides an opportunity to gain further insights into the pathobiology of diseases associated with this gene. The ARHGEF10 mutation does not, however, by itself account for all cases of polyneuropathy in Leonbergers or Saint Bernards.
Zdroje
1. MartynCN, HughesRA (1997) Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62: 310–318.
2. PareysonD (1999) Charcot-marie-tooth disease and related neuropathies: Molecular basis for distinction and diagnosis. Muscle Nerve 22: 1498–1509.
3. Meyer Zu HorsteG, NaveKA (2006) Animal models of inherited neuropathies. Curr Opin Neurol 19: 464–473.
4. SheltonGD (2007) What's new in muscle and peripheral nerve diseases? Vet Comp Orthop Traumatol 20: 249–255.
5. CoatesJR, O'BrienDP (2004) Inherited peripheral neuropathies in dogs and cats. Vet Clin North Am Small Anim Pract 34: 1361–1401.
6. GrangerN (2011) Canine inherited motor and sensory neuropathies: An updated classification in 22 breeds and comparison to charcot-marie-tooth disease. Vet J 188: 274–285.
7. DrogemullerC, BeckerD, KesslerB, KemterE, TetensJ, et al. (2010) A deletion in the N-myc downstream regulated gene 1 (NDRG1) gene in greyhounds with polyneuropathy. PLoS One 5: e11258.
8. BruunCS, JaderlundKH, BerendtM, JensenKB, SpodsbergEH, et al. (2013) A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in alaskan malamutes with polyneuropathy. PLoS One 8: e54547.
9. SheltonGD, PodellM, PonceletL, SchatzbergS, PattersonE, et al. (2003) Inherited polyneuropathy in leonberger dogs: A mixed or intermediate form of charcot-marie-tooth disease? Muscle Nerve 27: 471–477.
10. Hultin JaderlundK, Baranowska KorbergI, NodtvedtA (2011) Inherited polyneuropathy in leonberger dogs. J Vet Intern Med 25: 997–1002.
11. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.
12. AulchenkoYS, RipkeS, IsaacsA, van DuijnCM (2007) GenABEL: An R library for genome-wide association analysis. Bioinformatics 23: 1294–1296.
13. VerhoevenK, De JongheP, Van de PutteT, NelisE, ZwijsenA, et al. (2003) Slowed conduction and thin myelination of peripheral nerves associated with mutant rho guanine-nucleotide exchange factor 10. Am J Hum Genet 73: 926–932.
14. Etienne-MannevilleS, HallA (2002) Rho GTPases in cell biology. Nature 420: 629–635.
15. FeltriML, SuterU, RelvasJB (2008) The function of RhoGTPases in axon ensheathment and myelination. Glia 56: 1508–1517.
16. StendelC, RoosA, DeconinckT, PereiraJ, CastagnerF, et al. (2007) Peripheral nerve demyelination caused by a mutant rho GTPase guanine nucleotide exchange factor, frabin/FGD4. Am J Hum Genet 81: 158–164.
17. DelagueV, JacquierA, HamadoucheT, PoitelonY, BaudotC, et al. (2007) Mutations in FGD4 encoding the rho GDP/GTP exchange factor FRABIN cause autosomal recessive charcot-marie-tooth type 4H. Am J Hum Genet 81: 1–16.
18. ChayaT, ShibataS, TokuharaY, YamaguchiW, MatsumotoH, et al. (2011) Identification of a negative regulatory region for the exchange activity and characterization of T332I mutant of rho guanine nucleotide exchange factor 10 (ARHGEF10). J Biol Chem 286: 29511–29520.
19. MohlM, WinklerS, WielandT, LutzS (2006) Gef10–the third member of a rho-specific guanine nucleotide exchange factor subfamily with unusual protein architecture. Naunyn Schmiedebergs Arch Pharmacol 373: 333–341.
20. BraundKG, SteinbergHS, ShoresA, SteissJE, MehtaJR, et al. (1989) Laryngeal paralysis in immature and mature dogs as one sign of a more diffuse polyneuropathy. J Am Vet Med Assoc 194: 1735–1740.
21. GaberCE, AmisTC, LeCouteurRA (1985) Laryngeal paralysis in dogs: A review of 23 cases. J Am Vet Med Assoc 186: 377–380.
22. JefferyND, TalbotCE, SmithPM, BaconNJ (2006) Acquired idiopathic laryngeal paralysis as a prominent feature of generalised neuromuscular disease in 39 dogs. Vet Rec 158: 17.
23. StanleyBJ, HauptmanJG, FritzMC, RosensteinDS, KinnsJ (2010) Esophageal dysfunction in dogs with idiopathic laryngeal paralysis: A controlled cohort study. Vet Surg 39: 139–149.
24. VanhaesebrouckAE, CouturierJ, CauzinilleL, MizisinAP, SheltonGD, et al. (2008) Demyelinating polyneuropathy with focally folded myelin sheaths in a family of miniature schnauzer dogs. J Neurol Sci 275: 100–105.
25. Olby N. (2013) Tetraparesis. In: BSAVA (British Small Animal Veterinary Association) Manual of Canine and Feline Neurology: 274.
26. MelcangiRC, PanzicaG (2009) Neuroactive steroids: An update of their roles in central and peripheral nervous system. Psychoneuroendocrinology 34 Suppl 1: S1–8.
27. MelcangiRC, Garcia-SeguraLM, Mensah-NyaganAG (2008) Neuroactive steroids: State of the art and new perspectives. Cell Mol Life Sci 65: 777–797.
28. CarusoD, ScuratiS, RoglioI, NobbioL, SchenoneA, et al. (2008) Neuroactive steroid levels in a transgenic rat model of CMT1A neuropathy. J Mol Neurosci 34: 249–253.
29. Fex SvenningsenA, KanjeM (1999) Estrogen and progesterone stimulate schwann cell proliferation in a sex- and age-dependent manner. J Neurosci Res 57: 124–130.
30. ForsS (2007) Neuromuscular manifestations of hypothyoidism in dogs. EJCAP 17: 173–178.
31. JaggyA, OliverJE (1994) Neurologic manifestations of thyroid disease. Vet Clin North Am Small Anim Pract 24: 487–494.
32. JaggyA, OliverJE, FergusonDC, MahaffeyEA, GlausTJr (1994) Neurological manifestations of hypothyroidism: A retrospective study of 29 dogs. J Vet Intern Med 8: 328–336.
33. OevermannA, BleyT, KonarM, LangJ, VandeveldeM (2008) A novel leukoencephalomyelopathy of leonberger dogs. J Vet Intern Med 22: 467–471.
34. StephensM, SmithNJ, DonnellyP (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68: 978–989.
35. StephensM, DonnellyP (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73: 1162–1169.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2014 Číslo 10
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