Advertisement

Genes & Genomics

, Volume 41, Issue 1, pp 125–131 | Cite as

Mutations of ARX and non-syndromic intellectual disability in Chinese population

  • Yufei Wu
  • Huan Zhang
  • Xiaofen Liu
  • Zhangyan Shi
  • Hongling Li
  • Zhibin Wang
  • Xiaoyong Jie
  • Shaoping Huang
  • Fuchang Zhang
  • Junlin Li
  • Kejin ZhangEmail author
  • Xiaocai GaoEmail author
Research Article
  • 68 Downloads

Abstract

Mutations of Aristaless-related homeobox (ARX) gene were looked as the third cause of non-syndromic intellectual disability (NSID), while the boundary between true disease-causing mutations and non-disease-causing variants within this gene remains elusive. To investigate the relationship between ARX mutations and NSID, a panel comprising six reported causal mutations of the ARX was detected in 369 sporadic NSID patients and 550 random participants in Chinese. Two mutations, c.428_451 dup and p.G286S, may be disease-causing mutations for NSID, while p.Q163R and p.P353L showed a great predictive value in female NSID diagnosis with significant associations (X2 = 19.60, p = 9.54e−6 for p.Q163R; X2 = 25.70, p = 4.00e−07 for p.P353L), carriers of these mutations had an increased risk of NSID of more than fourfold. Detection of this panel also predicted significant associations between genetic variants of the ARX gene and NSID (p = 3.73e−4). The present study emphasized the higher genetic burden of the ARX gene on NSID in the Chinese population, molecular analysis of this gene should be considered for patients presenting NSID of unknown etiology.

Keywords

Non-syndromic intellectual disability Aristaless-related homeobox (ARX) Disease-causing mutation Genetic counseling 

Notes

Acknowledgements

We are grateful to all participants and our clinical collaborators for subject recruitment, evaluation and mutation scanning. This study was supported by grants from the Natural Science Foundation of China (No. 31371237) to Junlin Li, (No. 31340028), Kejin Zhang, and (No. 31100899) Zhangyan Shi. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

KJZ and XCG conceived and designed the experiments; HZ, XYJ, FCZ and SPH investigated, recruited and evaluated the patients and random sample; ZYS, YFW performed the experiments; KJZ and XCG analyzed the data; XFL, YFW and ZBW wrote the paper.

Compliance with ethical standards

Conflict of interest

Wu YF, Liu XF, Zhang H, Shi ZY, Li HL, Wang ZB, Jie XY, Huang SP, Zhang FC, Li JL, Zhagn KJ and Gao XC declare that they have no conflict to interest.

Ethical approval

This study had been approved by the Ethics Committee of Northwest University.

Informed consent

Written informed consent was obtained from all participants and/or their guardian in the study.

References

  1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249CrossRefGoogle Scholar
  2. Association for Retarded Citizens of the United States (1982) The prevalence of mental retardation. Wiley, New YorkGoogle Scholar
  3. Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D, Fauchereau F, Ben Jeema L, Zemni R, Vinet MC, Francis F et al (2002) ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 11:981–991CrossRefGoogle Scholar
  4. Cho G, Nasrallah MP, Lim Y, Golden JA (2012) Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations. Neurogenetics 13:23–29CrossRefGoogle Scholar
  5. Claes S, Gu XX, Legius E, Lorenzetti E, Marynen P, Fryns JP, Cassiman JJ, Raeymaekers P (1996) Linkage analysis in three families with nonspecific X-linked mental retardation. Am J Med Genet 64:137–146CrossRefGoogle Scholar
  6. Frints SG, Froyen G, Marynen P, Fryns JP (2002) X-linked mental retardation: vanishing boundaries between non-specific (MRX) and syndromic (MRXS) forms. Clin Genet 62:423–432CrossRefGoogle Scholar
  7. Friocourt G, Parnavelas JG (2010) Mutations in ARX result in several defects involving GABAergic neurons. Front Cell Neurosci 4:4Google Scholar
  8. Fullston T, Finnis M, Hackett A, Hodgson B, Brueton L, Baynam G, Norman A, Reish O, Shoubridge C, Gecz J (2011) Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. Clin Genet 80:510–522CrossRefGoogle Scholar
  9. Fulp CT, Cho G, Marsh ED, Nasrallah IM, Labosky PA, Golden JA (2008) Identification of Arx transcriptional targets in the developing basal forebrain. Hum Mol Genet 17:3740–3760CrossRefGoogle Scholar
  10. Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet 60(1):2–12Google Scholar
  11. Gecz J, Cloosterman D, Partington M (2006) ARX: a gene for all seasons. Curr Opin Genet Dev 16:308–316CrossRefGoogle Scholar
  12. Jemaa LB, des Portes V, Zemni R, Mrad R, Maazoul F, Beldjord C, Chaabouni H, Chelly J (1999) Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental retardation gene (MRX54). Am J Med Genet 85:276–282CrossRefGoogle Scholar
  13. Johnston JJ, Lewis KL, Ng D, Singh LN, Wynter J, Brewer C, Brooks BP, Brownell I, Candotti F, Gonsalves SG et al (2015) Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations. Am J Hum Genet 96:913–925CrossRefGoogle Scholar
  14. Kato M, Das S, Petras K, Kitamura K, Morohashi K, Abuelo DN, Barr M, Bonneau D, Brady AF, Carpenter NJ et al (2004) Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23:147–159CrossRefGoogle Scholar
  15. Kaufman L, Ayub M, Vincent JB (2010) The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2:182–209CrossRefGoogle Scholar
  16. LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC (2017) Exome sequencing covers> 98% of mutations identified on targeted next generation sequencing panels. PLoS ONE 12:e0170843CrossRefGoogle Scholar
  17. Laperuta C, Spizzichino L, D'Adamo P, Monfregola J, Maiorino A, D'Eustacchio A, Ventruto V, Neri G, D'Urso M, Chiurazzi P et al (2007) MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions. BMC Med Genet 8:25CrossRefGoogle Scholar
  18. Lee K, Ireland K, Bleeze M, Shoubridge C (2017) ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons. Neuroscience 357:220–231CrossRefGoogle Scholar
  19. Leonard H, Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 8:117–134CrossRefGoogle Scholar
  20. Marques I, Sa MJ, Soares G, Mota Mdo C, Pinheiro C, Aguiar L, Amado M, Soares C, Calado A, Dias P et al (2015) Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. Mol Genet Genomic Med 3:203–214CrossRefGoogle Scholar
  21. Marsh E, Fulp C, Gomez E, Nasrallah I, Minarcik J, Sudi J, Christian SL, Mancini G, Labosky P, Dobyns W et al (2009) Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. Brain 132:1563–1576CrossRefGoogle Scholar
  22. Nasrallah IM, Minarcik JC, Golden JA (2004) A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. J Cell Biol 167:411–416CrossRefGoogle Scholar
  23. Phillips MR, Zhang J, Shi Q, Song Z, Ding Z, Pang S, Li X, Zhang Y, Wang Z (2009) Prevalence, treatment, and associated disability of mental disorders in four provinces in China during 2001-05: an epidemiological survey. Lancet 373:2041–2053CrossRefGoogle Scholar
  24. Piton A, Redin C, Mandel JL (2013) XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet 93:368–383CrossRefGoogle Scholar
  25. Poirier K, Lacombe D, Gilbert-Dussardier B, Raynaud M, Desportes V, de Brouwer AP, Moraine C, Fryns JP, Ropers HH, Beldjord C et al (2006) Screening of ARX in mental retardation families: consequences for the strategy of molecular diagnosis. Neurogenetics 7:39–46CrossRefGoogle Scholar
  26. Reichenberg A, Cederlof M, McMillan A, Trzaskowski M, Kapara O, Fruchter E, Ginat K, Davidson M, Weiser M, Larsson H et al (2016) Discontinuity in the genetic and environmental causes of the intellectual disability spectrum. Proc Natl Acad Sci USA 113:1098–1103CrossRefGoogle Scholar
  27. Sauna ZE, Kimchi-Sarfaty C (2013) Synonymous mutations as a cause of human genetic disease. Wiley, ChichesterCrossRefGoogle Scholar
  28. Scheffer IE, Wallace RH, Phillips FL, Hewson P, Reardon K, Parasivam G, Stromme P, Berkovic SF, Gecz J, Mulley JC (2002) X-linked myoclonic epilepsy with spasticity and intellectual disability—mutation in the homeobox gene ARX. Neurology 59:348–356CrossRefGoogle Scholar
  29. Sherr EH (2003) The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr 15:567–571CrossRefGoogle Scholar
  30. Shoubridge C, Fullston T, Gecz J (2010) ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat 31:889–900CrossRefGoogle Scholar
  31. Stromme P, Sundet K, Mork C, Cassiman JJ, Fryns JP, Claes S (1999) X linked mental retardation and infantile spasms in a family: new clinical data and linkage to Xp11.4-Xp22.11. J Med Genet 36:374–378Google Scholar
  32. Stromme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lutcherath V, Gedeon AK, Wallace RH, Scheffer IE et al (2002) Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 30:441–445CrossRefGoogle Scholar
  33. Wang K (2016) Boosting the power of the sequence kernel association test by properly estimating its null distribution. Am J Hum Genet 99:104–114CrossRefGoogle Scholar
  34. Wang K, Fingert JH (2012) Statistical tests for detecting rare variants using variance-stabilising transformations. Ann Hum Genet 76:402–409CrossRefGoogle Scholar
  35. WHO (2003) Access to rehabilitation for the 600 million pepole living with disabilities [Internet]. World Health Organization, GenevaGoogle Scholar
  36. WHO (2007) The World Health Report 2007- A safer future global public health security in the 21st century. World Health Organization, GenevaGoogle Scholar
  37. Zhang F, Li R, Gao X, Zheng Z, Huang S, Song H, Xi H, Li F (2004) A investigation of mental retardation children aged 0–14 in Qinba Mountain areas. J Fourth Mil Med Univ 25:4Google Scholar
  38. Zhou S, Shi Z, Cui M, Li J, Ma Z, Shi Y, Zheng Z, Zhang F, Jin T, Geng T et al (2015) A new role for LOC101928437 in non-syndromic intellectual disability: findings from a family-based association test. PLoS ONE 10:e0135669CrossRefGoogle Scholar

Copyright information

© The Genetics Society of Korea and Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Key Laboratory of Resource Biology and Biotechnology in Western China (Ministry of Education), Institute of Population and HealthNorthwest UniversityXi’anChina
  2. 2.College of Public Management, Institute of Application PsychologyNorthwest UniversityXi’anChina
  3. 3.The 2nd Affiliated HospitalXi’an Jiaotong UniversityXi’anChina
  4. 4.Xi’an Cangning Psychiatric HospitalXi’anChina

Personalised recommendations