Human Genetics

, Volume 117, Issue 6, pp 536–544

Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly

  • Sarah A. Shoichet
  • Stella-Amrei Kunde
  • Petra Viertel
  • Can Schell-Apacik
  • Hubertus von Voss
  • Niels Tommerup
  • Hans-Hilger Ropers
  • Vera M. Kalscheuer
Original Investigation

Abstract

We have investigated the chromosome abnormalities in a female patient exhibiting a severe cognitive disability associated with complete agenesis of the corpus callosum and microcephaly. The patient carries a balanced de novo translocation t(2;14)(p22;q12), together with a neighbouring 720 kb inversion in chromosome 14q12. By combined fluorescence in situ hybridisation and Southern hybridisation, the distal inversion breakpoint on chromosome 14 was mapped to a region harbouring genes and ESTs derived predominantly from brain tissue. RT-PCR studies indicated that these transcripts comprise the 3′ ends of novel splice variants of the winged helix transcription factor FOXG1B (also referred to in previous studies as FOXG1A and FOXG1C, as well as Brain Factor 1), the mouse orthologue of which is essential for normal development of the telencephalon. Analysis of these novel FOXG1B transcripts indicated that they are all disrupted by the breakpoint in the patient. Moreover, we have identified novel orthologous Foxg1 transcripts in the mouse and other vertebrates, which validates the functional importance of these variants and provides a direct genetic link between the patient phenotype and that of the heterozygous Foxg1 knockout mice. These results, together with previously published studies on patients with similar disorders and proximal 14q deletions, strongly suggest that several disorders associated with malformations of the human brain may be directly caused by mutations or alterations in the FOXG1B gene.

Keywords

FOXG1 Agenesis of the corpus callosum Microcephaly Chromosome 14 Balanced translocation Mental retardation BF-1 

References

  1. Chong SS, Pack SD, Roschke AV, Tanigami A, Carrozzo R, Smith AC, Dobyns WB, Ledbetter DH (1997) A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet 6:147–155CrossRefPubMedGoogle Scholar
  2. Endris V, Wogatzky B, Leimer U, Bartsch D, Zatyka M, Latif F, Maher ER, Tariverdian G, Kirsch S, Karch D, Rappold GA (2002) The novel Rho-GTPase activating gene MEGAP/srGAP3 has a putative role in severe mental retardation. Proc Natl Acad Sci USA 99:11754–11759CrossRefPubMedGoogle Scholar
  3. Frangiskakis JM, Ewart AK, Morris CA, Mervis CB, Bertrand J, Robinson BF, Klein BP, Ensing GJ, Everett LA, Green ED, Proschel C, Gutowski NJ, Noble M, Atkinson DL, Odelberg SJ, Keating MT (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86:59–69CrossRefPubMedGoogle Scholar
  4. Grammatico P, de Sanctis S, di Rosa C, Cupilari F, del Porto G (1994) First case of deletion 14q11.2q13: clinical phenotype. Ann Genet 37:30–32PubMedGoogle Scholar
  5. Hanashima C, Shen L, Li SC, Lai E (2002) Brain factor-1 controls the proliferation and differentiation of neocortical progenitor cells through independent mechanisms. J Neurosci 22:6526–6536PubMedGoogle Scholar
  6. Hanashima C, Li SC, Shen L, Lai E, Fishell G (2004) Foxg1 suppresses early cortical cell fate. Science 303:56–59CrossRefPubMedGoogle Scholar
  7. Kamnasaran D, O‘Brien PC, Schuffenhauer S, Quarrell O, Lupski JR, Grammatico P, Ferguson-Smith MA, Cox DW (2001) Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes. Am J Med Genet 102:173–182CrossRefPubMedGoogle Scholar
  8. Murphy DB, Wiese S, Burfeind P, Schmundt D, Mattei MG, Schulz-Schaeffer W, Thies U (1994) Human brain factor 1, a new member of the fork head gene family. Genomics 21:551–557CrossRefPubMedGoogle Scholar
  9. Ramakers GJ (2002) Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 25:191–199CrossRefPubMedGoogle Scholar
  10. Ramelli GP, Remonda L, Lovblad KO, Hirsiger H, Moser H (2000) Abnormal myelination in a patient with deletion 14q11.2q13.1. Pediatr Neurol 23:170–172CrossRefPubMedGoogle Scholar
  11. Schuffenhauer S, Leifheit HJ, Lichtner P, Peters H, Murken J, Emmerich P (1999) De novo deletion (14)(q11.2q13) including PAX9: clinical and molecular findings. J Med Genet 36:233–236PubMedGoogle Scholar
  12. Siebert PD, Chenchik A, Kellogg DE, Lukyanov KA, Lukyanov SA (1995) An improved PCR method for walking in uncloned genomic DNA. Nucleic Acids Res 23:1087–1088PubMedGoogle Scholar
  13. Stevenson RE, Schwartz CE, Schroer RJ (2000) X-Linked Mental Retardation. Oxford University Press, New YorkGoogle Scholar
  14. Su PH, Chen SJ, Lee IC, Wang KL, Chen JY, Hung HM, Lee CF (2004) Interstitial deletion of chromosome 14q in a Taiwanese infant with microcephaly. J Formos Med Assoc 103:385–387PubMedGoogle Scholar
  15. Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995–1013PubMedGoogle Scholar
  16. Wirth J, Nothwang HG, van der Maarel S, Menzel C, Borck G, Lopez-Pajares I, Brondum-Nielsen K, Tommerup N, Bugge M, Ropers HH, Haaf T (1999) Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes. J Med Genet 36:271–278PubMedGoogle Scholar
  17. Xuan S, Baptista CA, Balas G, Tao W, Soares VC, Lai E (1995) Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres. Neuron 14:1141–1152CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Sarah A. Shoichet
    • 1
  • Stella-Amrei Kunde
    • 1
  • Petra Viertel
    • 1
  • Can Schell-Apacik
    • 2
  • Hubertus von Voss
    • 2
  • Niels Tommerup
    • 3
  • Hans-Hilger Ropers
    • 1
  • Vera M. Kalscheuer
    • 1
  1. 1.Max-Planck-Institute for Molecular GeneticsBerlinGermany
  2. 2.Medizinische GenetikKinderzentrum MünchenMunichGermany
  3. 3.Department of Medical Biochemistry and Genetics, Wilhelm Johannsen Centre for Functional Genome ResearchThe Panum InstituteCopenhagenDenmark

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