Periventricular heterotopia in 6q terminal deletion syndrome

Role of the C6orf70 gene

Valerio Conti, Aurelie Carabalona, Emilie Pallesi-Pocachard, Elena Parrini, Richard J. Leventer, Emmanuelle Buhler, George McGillivray, François J. Michel, Pasquale Striano, Davide Mei, Françoise Watrin, Stefano Lise, Alistair T. Pagnamenta, Jenny C. Taylor, Usha Kini, Jill Clayton-Smith, Francesca Novara, Orsetta Zuffardi, William B. Dobyns, Ingrid E. Scheffer & 6 others Stephen P. Robertson, Samuel F. Berkovic, Alfonso Represa, David A. Keays, Carlos Cardoso, Renzo Guerrini

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.

Original languageEnglish
Pages (from-to)3378-3394
Number of pages17
JournalBrain
Volume136
Issue number11
DOIs
Publication statusPublished - 2013

Fingerprint

Periventricular Nodular Heterotopia
Chromosomes, Human, Pair 6
Open Reading Frames
Chromosome Mapping
Genes
Haploinsufficiency
Mutation
Epilepsy
Brain
Filamins
ADP-Ribosylation Factors
Agenesis of Corpus Callosum
Exome
Guanine Nucleotide Exchange Factors
Comparative Genomic Hybridization
Lateral Ventricles
Neocortex
Human Chromosomes
Missense Mutation
Ataxia

Keywords

  • 6q terminal deletion syndrome
  • Brain malformations
  • C6orf70 gene
  • Epilepsy
  • Periventricular nodular heterotopia

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Conti, V., Carabalona, A., Pallesi-Pocachard, E., Parrini, E., Leventer, R. J., Buhler, E., ... Guerrini, R. (2013). Periventricular heterotopia in 6q terminal deletion syndrome: Role of the C6orf70 gene. Brain, 136(11), 3378-3394. https://doi.org/10.1093/brain/awt249

Periventricular heterotopia in 6q terminal deletion syndrome : Role of the C6orf70 gene. / Conti, Valerio; Carabalona, Aurelie; Pallesi-Pocachard, Emilie; Parrini, Elena; Leventer, Richard J.; Buhler, Emmanuelle; McGillivray, George; Michel, François J.; Striano, Pasquale; Mei, Davide; Watrin, Françoise; Lise, Stefano; Pagnamenta, Alistair T.; Taylor, Jenny C.; Kini, Usha; Clayton-Smith, Jill; Novara, Francesca; Zuffardi, Orsetta; Dobyns, William B.; Scheffer, Ingrid E.; Robertson, Stephen P.; Berkovic, Samuel F.; Represa, Alfonso; Keays, David A.; Cardoso, Carlos; Guerrini, Renzo.

In: Brain, Vol. 136, No. 11, 2013, p. 3378-3394.

Research output: Contribution to journalArticle

Conti, V, Carabalona, A, Pallesi-Pocachard, E, Parrini, E, Leventer, RJ, Buhler, E, McGillivray, G, Michel, FJ, Striano, P, Mei, D, Watrin, F, Lise, S, Pagnamenta, AT, Taylor, JC, Kini, U, Clayton-Smith, J, Novara, F, Zuffardi, O, Dobyns, WB, Scheffer, IE, Robertson, SP, Berkovic, SF, Represa, A, Keays, DA, Cardoso, C & Guerrini, R 2013, 'Periventricular heterotopia in 6q terminal deletion syndrome: Role of the C6orf70 gene', Brain, vol. 136, no. 11, pp. 3378-3394. https://doi.org/10.1093/brain/awt249
Conti V, Carabalona A, Pallesi-Pocachard E, Parrini E, Leventer RJ, Buhler E et al. Periventricular heterotopia in 6q terminal deletion syndrome: Role of the C6orf70 gene. Brain. 2013;136(11):3378-3394. https://doi.org/10.1093/brain/awt249
Conti, Valerio ; Carabalona, Aurelie ; Pallesi-Pocachard, Emilie ; Parrini, Elena ; Leventer, Richard J. ; Buhler, Emmanuelle ; McGillivray, George ; Michel, François J. ; Striano, Pasquale ; Mei, Davide ; Watrin, Françoise ; Lise, Stefano ; Pagnamenta, Alistair T. ; Taylor, Jenny C. ; Kini, Usha ; Clayton-Smith, Jill ; Novara, Francesca ; Zuffardi, Orsetta ; Dobyns, William B. ; Scheffer, Ingrid E. ; Robertson, Stephen P. ; Berkovic, Samuel F. ; Represa, Alfonso ; Keays, David A. ; Cardoso, Carlos ; Guerrini, Renzo. / Periventricular heterotopia in 6q terminal deletion syndrome : Role of the C6orf70 gene. In: Brain. 2013 ; Vol. 136, No. 11. pp. 3378-3394.
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abstract = "Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.",
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author = "Valerio Conti and Aurelie Carabalona and Emilie Pallesi-Pocachard and Elena Parrini and Leventer, {Richard J.} and Emmanuelle Buhler and George McGillivray and Michel, {Fran{\cc}ois J.} and Pasquale Striano and Davide Mei and Fran{\cc}oise Watrin and Stefano Lise and Pagnamenta, {Alistair T.} and Taylor, {Jenny C.} and Usha Kini and Jill Clayton-Smith and Francesca Novara and Orsetta Zuffardi and Dobyns, {William B.} and Scheffer, {Ingrid E.} and Robertson, {Stephen P.} and Berkovic, {Samuel F.} and Alfonso Represa and Keays, {David A.} and Carlos Cardoso and Renzo Guerrini",
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AU - Conti, Valerio

AU - Carabalona, Aurelie

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AU - Parrini, Elena

AU - Leventer, Richard J.

AU - Buhler, Emmanuelle

AU - McGillivray, George

AU - Michel, François J.

AU - Striano, Pasquale

AU - Mei, Davide

AU - Watrin, Françoise

AU - Lise, Stefano

AU - Pagnamenta, Alistair T.

AU - Taylor, Jenny C.

AU - Kini, Usha

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AU - Novara, Francesca

AU - Zuffardi, Orsetta

AU - Dobyns, William B.

AU - Scheffer, Ingrid E.

AU - Robertson, Stephen P.

AU - Berkovic, Samuel F.

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AU - Cardoso, Carlos

AU - Guerrini, Renzo

PY - 2013

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N2 - Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.

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