Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis

Bon, Bregje W.M. van; Koolen, David A.; Borgatti, Renato; Magee, Alex; García‐Miñaúr, Sixto; Rooms, Liesbeth; Reardon, William; Zollino, Marcella; Bonaglia, María Clara; Gregori, Manuela De; Novara, Francesca; Grasso, Rita; Ciccone, Roberto; Duyvenvoorde, Hermine A. van; Aalbers, Anna M.; Guerrini, Renzo; Fazzi, Elisa; Nillesen, Willy M.; McCullough, S; Kant, Sarina G.; Marcelis, Carlo; Pfundt, Rolph; Leeuw, Nicole de; Smeets, Dominique; Sistermans, Erik A.; Wit, J. M.; Hamel, B.C.J.; Brunner, Han G.; Kooy, R. Frank; Zuffardi, Orsetta; Vries, L.B.A. de

doi:10.1136/jmg.2007.055830

Cited by 87 publications

(114 citation statements)

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“…Critically, loss of RP58 in the CNS leads to a novel postnatal small-brain phenotype with loss of corpus callosum and cerebellar vermis hypoplasia, which resembles the human microencephaly phenotype linked to loss of chromosome-1qter. [9][10][11][12] Defective organization of the cerebral cortex in RP58 mutants. In order to confirm and extend the reported localization of RP58 in the mouse brain 15 and to interpret correctly the phenotypes described above, we performed antisense RNA in situ hybridization analyses on sections of mouse brains at different stages of development.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, deletion of the distal end of human chromosome-1q is linked to microcephaly with agenesis of the corpus callosum (e.g. [9][10][11], and a critical region contains only a handful of genes, including RP58. 9-12 RP58, also known as ZNF238, 13 encodes a transcription factor with a BTB/POZ and four zincfinger domains 14 that is highly conserved (495%) between humans and mice, suggesting conserved functions.…”

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RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

et al. 2011

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Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects. Using a novel conditional RP58 allele here we show that its CNS-specific loss yields a novel postnatal phenotype: microencephaly, agenesis of the corpus callosum and cerebellar hypoplasia that resembles the chr1qter deletion microcephaly syndrome in human. RP58 mutant brains maintain precursor pools but have reduced neuronal and increased glial differentiation. Well-timed downregulation of pax6, ngn2 and neuroD1 depends on RP58 mediated transcriptional repression, ngn2 and neuroD1 being direct targets. Thus, RP58 may act to favor neuronal differentiation and brain growth by coherently repressing multiple proneurogenic genes in a timely manner. The cerebral cortex undergoes rapid expansion during embryogenesis, when neuronal layers are formed. Two main types of precursors exist in the developing neocortex: multipotent radial glial stem/progenitor cells (RGCs) in the ventricular zone (VZ) and derived intermediate neurogenic progenitors (INPs) in the subventricular zone (SVZ). 1-3 INPs divide 1-2 times and only give rise to neurons, with regulation of their number proposed to contribute to cortical expansion. [1][2][3][4][5][6] Molecularly, a sequence of key transcription factors, Pax6-4Ngn2-4Tbr2-4NeuroD1-4Tbr1, promotes cortical neurogenesis. 7 Among these, Ngn2 is required for transition from early Pax6 þ radial glia to Tbr2 þ INPs, as well as for expansion of INPs, whereas NeuroD1 is expressed in INPs and early-differentiating neurons. 7,8 How their sequential timed expression is regulated to promote the development of normal-sized cortices is unknown.The development of human microcephaly likely results from abnormal cortical precursor behavior. Interestingly, deletion of the distal end of human chromosome-1q is linked to microcephaly with agenesis of the corpus callosum (e.g. 9-11), and a critical region contains only a handful of genes, including RP58. 9-12 RP58, also known as ZNF238, 13 encodes a transcription factor with a BTB/POZ and four zincfinger domains 14 that is highly conserved (495%) between humans and mice, suggesting conserved functions.Previous work has shown that RP58 is expressed in mouse brain precursors and neurons, 15 and that its complete loss leads to defects in cortical and hippocampal development. 16 Critically, perinatal death of conventional knockout (KO) mice 16 precludes analyses in postnatal stages. Furthermore, the reported defects in cell-cycle exit, and in Pax6 þ and Tbr2 þ populations, were deduced from analyses at late corticogenesis stages after embryonic day (E) 16.5, precluding any conclusions on early defects and not provi...

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Section: Resultsmentioning

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confidence: 99%

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

et al. 2011

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“…3 Several studies have investigated the critical region for 1q44 subtelomeric deletion syndrome and found that the core phenotypic features of 1q44 subtelomeric deletion syndrome are microcephaly, abnormalities of the corpus callosum (ACC) and seizures. [4][5][6][7][8][9][10][11][12][13][14][15][16] Recently, Ballif et al 17 analyzed patients with microdeletions of 1q44 and proposed certain genes that may be responsible for individual features.…”

Section: Introductionmentioning

confidence: 99%

Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination

et al. 2012

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“…[1][2][3][4][5][6][7][8] Even for patients with an overlapping deletion, the phenotype varies considerably. So far, no direct association has been identified between the phenotype and the deleted genes.…”

Section: Introductionmentioning

confidence: 99%

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

et al. 2013

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Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis

Cited by 87 publications

References 20 publications

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

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