Recessive Mutations in Implicate β-III Spectrin in Both Cognitive and Motor Development

English version České info

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

Vyšlo v časopise: Recessive Mutations in Implicate β-III Spectrin in Both Cognitive and Motor Development. PLoS Genet 8(12): e32767. doi:10.1371/journal.pgen.1003074
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003074

Souhrn

Zdroje

1. PerrottaS, GallagherPG, MohandasN (2008) Hereditary spherocytosis. Lancet 372: 1411–1426.

2. BainesAJ (2010) The spectrin-ankyrin-4.1-adducin membrane skeleton: adapting eukaryotic cells to the demands of animal life. Protoplasma 244: 99–131.

3. GoodmanSR, ZimmerWE, ClarkMB, ZagonIS, BarkerJE, et al. (1995) Brain spectrin: of mice and men. Brain Res Bull 36: 593–606.

4. IkedaY, DickKA, WeatherspoonMR, GincelD, ArmbrustKR, et al. (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38: 184–190.

5. NeeLE, HigginsJJ (1997) Should spinocerebellar ataxia type 5 be called Lincoln ataxia? Neurology 49: 298–302.

6. HigginsJJ (2010) Sca5 or Lincoln ataxia? Neurology 74: 1836 author reply 1837–1838.

7. RanumLP, KruegerKA, SchutLJ (2010) Abraham Lincoln may have had sca type 5. Neurology 74: 1836–1837 author reply 1837-1838.

8. StevaninG, HermanA, BriceA, DurrA (1999) Clinical and MRI findings in spinocerebellar ataxia type 5. Neurology 53: 1355–1357.

9. BurkK, ZuhlkeC, KonigIR, ZieglerA, SchwingerE, et al. (2004) Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred. Neurology 62: 327–329.

10. JacksonM, SongW, LiuMY, JinL, Dykes-HobergM, et al. (2001) Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410: 89–93.

11. IpsaroJJ, HuangL, GutierrezL, MacDonaldRI (2008) Molecular epitopes of the ankyrin-spectrin interaction. Biochemistry 47: 7452–7464.

12. NicolasG, PedroniS, FournierC, GauteroH, CraescuC, et al. (1998) Spectrin self-association site: characterization and study of beta-spectrin mutations associated with hereditary elliptocytosis. Biochem J 332(Pt 1): 81–89.

13. PerkinsEM, ClarksonYL, SabatierN, LonghurstDM, MillwardCP, et al. (2010) Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 30: 4857–4867.

14. ClarksonYL, GillespieT, PerkinsEM, LyndonAR, JacksonM (2010) Beta-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from the Golgi. Hum Mol Genet 19: 3634–3641.

15. SaitsuH, TohyamaJ, KumadaT, EgawaK, HamadaK, et al. (2010) Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am J Hum Genet 86: 881–891.

16. BarkerGR, BirdF, AlexanderV, WarburtonEC (2007) Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci 27: 2948–2957.

17. DeVitoLM, EichenbaumH (2010) Distinct contributions of the hippocampus and medial prefrontal cortex to the “what-where-when” components of episodic-like memory in mice. Behav Brain Res 215: 318–325.

18. StensonPD, BallEV, HowellsK, PhillipsAD, MortM, et al. (2009) The Human Gene Mutation Database: providing a comprehensive central mutation database for molecular diagnostics and personalized genomics. Hum Genomics 4: 69–72.

19. GaoY, PerkinsEM, ClarksonYL, TobiaS, LyndonAR, et al. (2011) beta-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis. J Neurosci 31: 16581–16590.

20. DiamondA (2000) Close interrelation of motor development and cognitive development and of the cerebellum and prefrontal cortex. Child Dev 71: 44–56.

21. BarkerGR, WarburtonEC (2011) When is the hippocampus involved in recognition memory? J Neurosci 31: 10721–10731.

22. FiezJA (1996) Cerebellar contributions to cognition. Neuron 16: 13–15.

23. StankewichMC, TseWT, PetersLL, Ch'ngY, JohnKM, et al. (1998) A widely expressed betaIII spectrin associated with Golgi and cytoplasmic vesicles. Proc Natl Acad Sci U S A 95: 14158–14163.

24. StankewichMC, GwynnB, ArditoT, JiL, KimJ, et al. (2010) Targeted deletion of betaIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. Proc Natl Acad Sci U S A 107: 6022–6027.

25. StankewichMC, CianciCD, StabachPR, JiL, NathA, et al. (2011) Cell organization, growth, and neural and cardiac development require alphaII-spectrin. J Cell Sci 124: 3956–3966.

26. ZhouD, LambertS, MalenPL, CarpenterS, BolandLM, et al. (1998) AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J Cell Biol 143: 1295–1304.

27. LunterG, GoodsonM (2011) Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res 21: 936–939.

28. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760.

29. AlbersCA, LunterG, MacArthurDG, McVeanG, OuwehandWH, et al. (2011) Dindel: accurate indel calls from short-read data. Genome Res 21: 961–973.

30. FlicekP, AmodeMR, BarrellD, BealK, BrentS, et al. (2011) Ensembl 2011. Nucleic Acids Res 39: D800–806.

31. SherryST, WardM, SirotkinK (1999) dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res 9: 677–679.

32. 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.

33. QuinlanAR, HallIM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842.

34. WangK, LiM, HakonarsonH (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38: e164.

35. KumarP, HenikoffS, NgPC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4: 1073–1081.

36. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249.

37. CooperGM, StoneEA, AsimenosG, GreenED, BatzoglouS, et al. (2005) Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15: 901–913.

38. DavydovEV, GoodeDL, SirotaM, CooperGM, SidowA, et al. (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6: e1001025 doi:10.1371/journal.pcbi.1001025.

39. WijetungeLS, TillSM, GillingwaterTH, InghamCA, KindPC (2008) mGluR5 regulates glutamate-dependent development of the mouse somatosensory cortex. J Neurosci 28: 13028–13037.