DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism

English version České info

Autism Spectrum Disorder (ASD) is a common behaviorally defined condition noted by impairments in social reciprocity and communicative abilities and exaggerated repetitive behaviors and stereotyped interests. Individuals with ASD frequently have a larger and more rapidly growing brain than their typically developing peers. Given the widely documented heritability suggesting that ASD is predominantly a genetic condition and the well-established link between ASD and abnormal brain growth patterns, genes involved in brain growth would be excellent candidates to study regarding ASD. One such candidate is DUF1220, a highly copy number polymorphic protein domain that we have previously linked to brain evolution and brain size. However, due to the extreme copy number variability of DUF1220, it has not been directly investigated in previous genome wide polymorphism studies searching for genes important in ASD. Here we show that, in individuals with ASD, 1) DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies, and 2) the copy number of CON1 is associated, in a linear dose-response manner, with increased severity of each of the three primary symptoms of ASD: as CON1 copy number increases each of the three primary symptoms of ASD (impaired social reciprocity, impaired communicative ability and increased repetitive behaviors) become incrementally worse.

Vyšlo v časopise: DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004241
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004241

Souhrn

Zdroje

1. Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006 (2009) Morb Mortal Wkly Rep Surveill Summ Wash DC 2002. 58: 1–20.

2. CourchesneE, CarperR, AkshoomoffN (2003) Evidence of brain overgrowth in the first year of life in autism. JAMA J Am Med Assoc 290: 337–344 doi:10.1001/jama.290.3.337

3. CourchesneE, MoutonPR, CalhounME, SemendeferiK, Ahrens-BarbeauC, et al. (2011) Neuron number and size in prefrontal cortex of children with autism. JAMA J Am Med Assoc 306: 2001–2010 doi:10.1001/jama.2011.1638

4. NordahlCW, LangeN, LiDD, BarnettLA, LeeA, et al. (2011) Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders. Proc Natl Acad Sci U S A 108: 20195–20200 doi:10.1073/pnas.1107560108

5. DavisJM, KeeneyJG, SikelaJM, HepburnS (2013) Mode of genetic inheritance modifies the association of head circumference and autism-related symptoms: a cross-sectional study. PLoS ONE 8: e74940 doi:10.1371/journal.pone.0074940

6. RojasDC, PetersonE, WinterrowdE, ReiteML, RogersSJ, et al. (2006) Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiatry 6: 56 doi:10.1186/1471-244X-6-56

7. NordenbækC, JørgensenM, KyvikKO, BilenbergN (2013) A Danish population-based twin study on autism spectrum disorders. Eur Child Adolesc Psychiatry doi:10.1007/s00787-013-0419-5

8. GeschwindDH (2011) Genetics of autism spectrum disorders. Trends Cogn Sci 15: 409–416 doi:10.1016/j.tics.2011.07.003

9. PopescoMC, MaclarenEJ, HopkinsJ, DumasL, CoxM, et al. (2006) Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains. Science 313: 1304–1307 doi:10.1126/science.1127980

10. DumasLJ, O'BlenessMS, DavisJM, DickensCM, AndersonN, et al. (2012) DUF1220-domain copy number implicated in human brain-size pathology and evolution. Am J Hum Genet 91: 444–454 doi:10.1016/j.ajhg.2012.07.016

11. DumasL, KimYH, Karimpour-FardA, CoxM, HopkinsJ, et al. (2007) Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res 17: 1266–1277 doi:10.1101/gr.6557307

12. O'BlenessMS, DickensCM, DumasLJ, Kehrer-SawatzkiH, WyckoffGJ, et al. (2012) Evolutionary history and genome organization of DUF1220 protein domains. G3 Bethesda Md 2: 977–986 doi:10.1534/g3.112.003061

13. CrespiBJ, CroftsHJ (2012) Association testing of copy number variants in schizophrenia and autism spectrum disorders. J Neurodev Disord 4: 15 doi:10.1186/1866-1955-4-15

14. GirirajanS, DennisMY, BakerC, MaligM, CoeBP, et al. (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92: 221–237 doi:10.1016/j.ajhg.2012.12.016

15. DumasL, SikelaJM (2009) DUF1220 domains, cognitive disease, and human brain evolution. Cold Spring Harb Symp Quant Biol 74: 375–382 doi:10.1101/sqb.2009.74.025

16. O'BlenessM, SearlesVB, VarkiA, GagneuxP, SikelaJM (2012) Evolution of genetic and genomic features unique to the human lineage. Nat Rev Genet 13: 853–866 doi:10.1038/nrg3336

17. CourchesneE, PierceK (2005) Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr Opin Neurobiol 15: 225–230 doi:10.1016/j.conb.2005.03.001

18. NelsonDL, OrrHT, WarrenST (2013) The unstable repeats–three evolving faces of neurological disease. Neuron 77: 825–843 doi:10.1016/j.neuron.2013.02.022

19. WalkerFO (2007) Huntington's disease. The Lancet 369: 218–228 doi:10.1016/S0140-6736(07)60111-1

20. WillemsenR, LevengaJ, OostraBA (2011) CGG repeat in the FMR1 gene: size matters. Clin Genet 80: 214–225 doi:10.1111/j.1399-0004.2011.01723.x

21. LajonchereCM (2010) Changing the Landscape of Autism Research: The Autism Genetic Resource Exchange. Neuron 68: 187–191 doi:10.1016/j.neuron.2010.10.009

22. ConstantinoJN, ZhangY, FrazierT, AbbacchiAM, LawP (2010) Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry 167: 1349–1356 doi:10.1176/appi.ajp.2010.09101470

23. SchumannCM, BarnesCC, LordC, CourchesneE (2009) Amygdala enlargement in toddlers with autism related to severity of social and communication impairments. Biol Psychiatry 66: 942–949 doi:10.1016/j.biopsych.2009.07.007