Skip to main content
SpringerLink
Log in

Population and Computational Analysis of the MGEA6 P521A Variation as a Risk Factor for Familial Idiopathic Basal Ganglia Calcification (Fahr’s Disease)

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

An Erratum to this article was published on 29 January 2011

Abstract

Familial idiopathic basal ganglia calcification, also known as “Fahr’s disease” (FD), is a neuropsychiatric disorder with autosomal dominant pattern of inheritance and characterized by symmetric basal ganglia calcifications and, occasionally, other brain regions. Currently, there are three loci linked to this devastating disease. The first one (IBGC1) is located in 14q11.2-21.3 and the other two have been identified in 2q37 (IBGC2) and 8p21.1-q11.13 (IBGC3). Further studies identified a heterozygous variation (rs36060072) which consists in the change of the cytosine to guanine located at MGEA6/CTAGE5 gene, present in all of the affected large American family linked to IBGC1. This missense substitution, which induces changes of a proline to alanine at the 521 position (P521A), in a proline-rich and highly conserved protein domain was considered a rare variation, with a minor allele frequency (MAF) of 0.0058 at the US population. Considering that the population frequency of a given variation is an indirect indicative of potential pathogenicity, we screened 200 chromosomes in a random control set of Brazilian samples and in two nuclear families, comparing with our previous analysis in a US population. In addition, we accomplished analyses through bioinformatics programs to predict the pathogenicity of such variation. Our genetic screen found no P521A carriers. Polling these data together with the previous study in the USA, we have now a MAF of 0.0036, showing that this mutation is very rare. On the other hand, the bioinformatics analysis provided conflicting findings. There are currently various candidate genes and loci that could be involved with the underlying molecular basis of FD etiology, and other groups suggested the possible role played by genes in 2q37, related to calcium metabolism, and at chromosome 8 (NRG1 and SNTG1). Additional mutagenesis and in vivo studies are necessary to confirm the pathogenicity for variation in the P521A MGEA6.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  • Comtesse N, Reus K, Meese E (2001) The MGEA6 multigene family has an active locus on14q and at least nine pseudogenes no different chromosomes. Genomics 75:1–6

    Article  Google Scholar 

  • Comtesse N, Niedermayer I, Glass B et al (2002) MGEA6 is tumor-specific overexpressed and frequently recognized by patient-serum antibodies. Oncogene 21:239–247

    Article  CAS  PubMed  Google Scholar 

  • Dai X, Gao Y, Xu Z et al. (2010) Identification of a novel genetic locus on chromosome 8p21.1-q11.23 for idiopathic basal ganglia calcification. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.31102

  • Di YM, Chan E, Wei MQ, Liu JP, Zhou SF (2009) Prediction of deleterious non-synonymous single-nucleotide polymorphisms of human uridine diphosphate glucuronosyltransferase genes. AAPS J 11:469–480

    Article  CAS  PubMed  Google Scholar 

  • Dorfman R, Nalpathamkalam T, Taylor C et al (2010) Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet 77:464–473

    Article  CAS  PubMed  Google Scholar 

  • Ferrer-Costa C, Gelpí CL, Zamakola L, Parraga I, Cruz X, Orozoco X (2005) PMUT: a web-based tool for the annotation of pathological mutation on proteins. Struct Bioinform 21:3176–3178

    Article  CAS  Google Scholar 

  • Freudenberg-Hua Y, Freudenberg J, Kluck N, Cichon S, Propping P, Nothen MM (2003) Single nucleotide variation analysis in 65 candidate genes for CNS disorders in a representative sample of the European population. Genome Res 13:2271–2276

    Article  CAS  PubMed  Google Scholar 

  • Geschwind DH, Loginov M, Stern JM (1999) Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease). Am J Hum Genet 65:764–772

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Yan C (2008) Identification of deleterious non-synonymous single nucleotide polymorphisms using sequence-derived information. BMC Bioinform 9:1–8

    Article  CAS  Google Scholar 

  • Manyam BV (2005) What is and what is not ‘Fahr’s disease’. Parkinsonism Relat Disord 11:73–80

    Article  PubMed  Google Scholar 

  • Ng PC, Henikoff S (2006) Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet 7:61–80

    Article  CAS  PubMed  Google Scholar 

  • Oliveira JRM, Hopfer S, Papp J et al (2003) A genome wide scan for familial idiopathic basal ganglia calcification (Fahr’s disease) identifies new candidate regions and confirms genetic heterogeneity. Am J Hum Genet 5:570

    Google Scholar 

  • Oliveira JR, Spiteri E, Sobrido MJ et al (2004) Genetic heterogeneity in familial idiopathic basal ganglia calcification (“Fahr’s disease”). Neurology 63:2165–2167

    CAS  PubMed  Google Scholar 

  • Oliveira JR, Sobrido MJ, Spiteri E et al (2007) Analysis of candidate genes at the IBGC1 locus associated with idiopathic basal ganglia calcification (“Fahr’s disease”). J Mol Neurosci 33:151–154

    Article  CAS  PubMed  Google Scholar 

  • Oliveira JR, Lima Filho JL, Zatz M (2009) Identical twins with idiopathic basal ganglia calcification (“Fahr’s disease”) presenting with a remarkably similar pattern of neuroimaging findings. Parkinsonism Relat Disord 5:396–397

    Article  Google Scholar 

  • Saillour Y, Zanni G, Des Portes V et al (2007) Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptator protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia. J Med Genet 11:739–744

    Article  Google Scholar 

  • Usener D, Schadendorf D, Kock J, Dubel S, Eichmuller S (2003) cTAGE: a cutaneous T cell lymphoma associated antigen family with tumor specific splicing. J Investig Dermatol 121:198–206

    Article  CAS  PubMed  Google Scholar 

  • Volpato CB, De Grandi A, Buffone E et al (2009) 2q37 as a susceptibility locus for idiopathic basal ganglia calcification (IBGC) in a large South Tyrolean family. J Mol Neurosci 39:346–353

    Article  CAS  PubMed  Google Scholar 

  • Wszolek ZK, Baba Y, Mackenzie IR et al (2006) Autosomal dominant dystonia-plus with cerebral calcifications. Neurology 22:620–625

    Article  Google Scholar 

  • Zarrinpar A, Bhattacharyya RP, Lim WA (2003) The structure of proline recognition domains. Sci STKE 22:1–10

    Google Scholar 

Download references

Acknowledgments

We are deeply indebted to Dr. Cíntia Rocha, Dr. José Luiz de Lima Filho (LIKA), and Dr Constância Ayres (Aggeu Magalhães Research Center) for the support with sequencing experiments. We also thank Dr. Maria Rita Passos Bueno and Lilian Calabró dos Santos (University of São Paulo) for providing the control DNA samples. This study was supported by the following Brazilian funding agencies and academic bureaus: CNPq (Universal 2008-480149/2008-9), PROPESQ-UFPE, CAPES, and FACEPE (APQ-0997-4.01/08) and PIBIC-UFPE. J.R.M.O. holds a research fellowship from the Brazilian National Research Council (CNPq, Brasília, Brazil) and from the John Simon Guggenheim Foundation (New York, USA).

Author information

Authors and Affiliations

  1. Keizo Asami Laboratory (LIKA), Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Roberta R. Lemos, Danyllo F. Oliveira & João R. M. Oliveira

  2. Human Genome Study Center, University of São Paulo, São Paulo, São Paulo, Brazil

    Mayana Zatz

  3. Neuropsychiatry Department, Federal University of Pernambuco (UFPE), 50670901, Recife, Pernambuco, Brazil

    João R. M. Oliveira

Authors
  1. Roberta R. Lemos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danyllo F. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mayana Zatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. João R. M. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to João R. M. Oliveira.

Additional information

Roberta R. Lemos and Danyllo F. Oliveira contributed equally to this work.

An erratum to this article can be found at http://dx.doi.org/10.1007/s12031-011-9495-5

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lemos, R.R., Oliveira, D.F., Zatz, M. et al. Population and Computational Analysis of the MGEA6 P521A Variation as a Risk Factor for Familial Idiopathic Basal Ganglia Calcification (Fahr’s Disease). J Mol Neurosci 43, 333–336 (2011). https://doi.org/10.1007/s12031-010-9445-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-010-9445-7

Keywords

Search

Navigation