#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Unraveling Genetic Modifiers in the Mouse Model of Absence Epilepsy


Absence seizures - also known as “petit-mal” - define a common form of epilepsy most prevalent in children, but also seen at other ages, and in related diseases such as juvenile myoclonic epilepsy. Absence seizures cause brief periods of unconsciousness, and are accompanied by characteristic abnormal brain waves called “spike-wave discharges” (SWD) due to their appearance in the electroencephalogram (EEG). Although few genes are known for human absence seizures, perhaps because the underlying genetics are complex, several laboratory rodent models exist, including one caused by mutation of a gene called Gria4. While studying Gria4, we noticed that a mouse strain called C3H can suppress or enhance the frequency and severity of Gria4-associated SWD in a perplexing manner; such effects are generally attributed to “modifier” genes. Here we identify a novel modifier – called “pecanex-like 2”, or Pcnxl2 for short – that reduces the severity of SWD in the C3H substrain in which the Gria4 mutation originally arose. This finding directed us to use of related substrains to locate additional modifiers, one of which has an even more profound effect on SWD episodes. Modifier genes, nature's way of controlling seizure severity, are promising targets for better understanding seizure mechanisms and potential new therapies in the future.


Vyšlo v časopise: Unraveling Genetic Modifiers in the Mouse Model of Absence Epilepsy. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004454
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004454

Souhrn

Absence seizures - also known as “petit-mal” - define a common form of epilepsy most prevalent in children, but also seen at other ages, and in related diseases such as juvenile myoclonic epilepsy. Absence seizures cause brief periods of unconsciousness, and are accompanied by characteristic abnormal brain waves called “spike-wave discharges” (SWD) due to their appearance in the electroencephalogram (EEG). Although few genes are known for human absence seizures, perhaps because the underlying genetics are complex, several laboratory rodent models exist, including one caused by mutation of a gene called Gria4. While studying Gria4, we noticed that a mouse strain called C3H can suppress or enhance the frequency and severity of Gria4-associated SWD in a perplexing manner; such effects are generally attributed to “modifier” genes. Here we identify a novel modifier – called “pecanex-like 2”, or Pcnxl2 for short – that reduces the severity of SWD in the C3H substrain in which the Gria4 mutation originally arose. This finding directed us to use of related substrains to locate additional modifiers, one of which has an even more profound effect on SWD episodes. Modifier genes, nature's way of controlling seizure severity, are promising targets for better understanding seizure mechanisms and potential new therapies in the future.


Zdroje

1. KosobudAE, CrossSJ, CrabbeJC (1992) Neural sensitivity to pentylenetetrazol convulsions in inbred and selectively bred mice. Brain research 592: 122–128.

2. KosobudAE, CrabbeJC (1990) Genetic correlations among inbred strain sensitivities to convulsions induced by 9 convulsant drugs. Brain research 526: 8–16.

3. GoldenGT, SmithGG, FerraroTN, ReyesPF, KulpJK, et al. (1991) Strain differences in convulsive response to the excitotoxin kainic acid. Neuroreport 2: 141–144.

4. FrankelWN, TaylorL, BeyerB, TempelBL, WhiteHS (2001) Electroconvulsive thresholds of inbred mouse strains. Genomics 74: 306–312.

5. GoldenGT, FerraroTN, SmithGG, SnyderRL, JonesNL, et al. (2001) Acute cocaine-induced seizures: differential sensitivity of six inbred mouse strains. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 24: 291–299.

6. FerraroTN, GoldenGT, SmithGG, DeMuthD, BuonoRJ, et al. (2002) Mouse strain variation in maximal electroshock seizure threshold. Brain research 936: 82–86.

7. CoxGA, LutzCM, YangCL, BiemesderferD, BronsonRT, et al. (1997) Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91: 139–148.

8. KearneyJA, BuchnerDA, De HaanG, AdamskaM, LevinSI, et al. (2002) Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). Human molecular genetics 11: 2765–2775.

9. YangY, MahaffeyCL, BerubeN, MaddatuTP, CoxGA, et al. (2007) Complex seizure disorder caused by Brunol4 deficiency in mice. PLoS genetics 3: e124.

10. HawkinsNA, MartinMS, FrankelWN, KearneyJA, EscaygA (2011) Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus. Neurobiology of disease 41: 655–660.

11. HawkinsNA, KearneyJA (2012) Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA-Seq. Genes, brain, and behavior 11: 452–460.

12. BergrenSK, RutterED, KearneyJA (2009) Fine mapping of an epilepsy modifier gene on mouse Chromosome 19. Mammalian genome : official journal of the International Mammalian Genome Society 20: 359–366.

13. JorgeBS, CampbellCM, MillerAR, RutterED, GurnettCA, et al. (2011) Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility. Proceedings of the National Academy of Sciences of the United States of America 108: 5443–5448.

14. PapaleLA, BeyerB, JonesJM, SharkeyLM, TufikS, et al. (2009) Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice. Human molecular genetics 18: 1633–1641.

15. TanHO, ReidCA, SingleFN, DaviesPJ, ChiuC, et al. (2007) Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proceedings of the National Academy of Sciences of the United States of America 104: 17536–17541.

16. BeyerB, DeleuzeC, LettsVA, MahaffeyCL, BoumilRM, et al. (2008) Absence seizures in C3H/HeJ and knockout mice caused by mutation of the AMPA receptor subunit Gria4. Human molecular genetics 17: 1738–1749.

17. FrankelWN, BeyerB, MaxwellCR, PretelS, LettsVA, et al. (2005) Development of a new genetic model for absence epilepsy: spike-wave seizures in C3H/He and backcross mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 25: 3452–3458.

18. TokudaS, BeyerBJ, FrankelWN (2009) Genetic complexity of absence seizures in substrains of C3H mice. Genes, brain, and behavior 8: 283–289.

19. PazJT, BryantAS, PengK, FennoL, YizharO, et al. (2011) A new mode of corticothalamic transmission revealed in the Gria4(−/−) model of absence epilepsy. Nature neuroscience 14: 1167–1173.

20. MaksakovaIA, RomanishMT, GagnierL, DunnCA, van de LagemaatLN, et al. (2006) Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS genetics 2: e2.

21. Laboratory TSoTJ (1997) Handbook on Genetically Standardized JAX® Mice; Fox RR, Witham BA, editors. Bar Harbor: The Jackson Laboratory.

22. IshiharaH, TanakaI, WanH, NojimaK, YoshidaK (2004) Retrotransposition of limited deletion type of intracisternal A-particle elements in the myeloid leukemia Clls of C3H/He mice. Journal of radiation research 45: 25–32.

23. NellakerC, KeaneTM, YalcinB, WongK, AgamA, et al. (2012) The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome biology 13: R45.

24. LaBonneSG, SunithaI, MahowaldAP (1989) Molecular genetics of pecanex, a maternal-effect neurogenic locus of Drosophila melanogaster that potentially encodes a large transmembrane protein. Developmental biology 136: 1–16.

25. YamakawaT, YamadaK, SasamuraT, NakazawaN, KanaiM, et al. (2012) Deficient Notch signaling associated with neurogenic pecanex is compensated for by the unfolded protein response in Drosophila. Development 139: 558–567.

26. CermakT, DoyleEL, ChristianM, WangL, ZhangY, et al. (2011) Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic acids research 39: e82.

27. StanfordWL, HaqueS, AlexanderR, LiuX, LatourAM, et al. (1997) Altered proliferative response by T lymphocytes of Ly-6A (Sca-1) null mice. The Journal of experimental medicine 186: 705–717.

28. TylerAL, LuW, HendrickJJ, PhilipVM, CarterGW (2013) CAPE: an R package for combined analysis of pleiotropy and epistasis. PLoS computational biology 9: e1003270.

29. AllenAS, BerkovicSF, CossetteP, DelantyN, DlugosD, et al. (2013) De novo mutations in epileptic encephalopathies. Nature 501: 217–221.

30. OlivaMK, McGarrTC, BeyerBJ, GazinaE, KaplanDI, et al. (2014) Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy. Neurobiology of Disease

31. SmithR, SheppardK, DiPetrilloK, ChurchillG (2009) Quantitative trait locus analysis using J/qtl. Methods in molecular biology 573: 175–188.

32. LuedersKK, FrankelWN, MietzJA, KuffEL (1993) Genomic mapping of intracisternal A-particle proviral elements. Mammalian genome : official journal of the International Mammalian Genome Society 4: 69–77.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#