OFCD syndrome and extraembryonic defects are revealed by conditional mutation of the Polycomb-group repressive complex 1.1 (PRC1.1) gene BCOR

Hamline, Michelle Y.; Corcoran, Connie M.; Wamstad, Joseph A.; Milétich, Isabelle; Feng, Jifan; Lohr, Jamie L.; Hemberger, Myriam; Sharpe, Paul T.; Gearhart, Micah D.; Bardwell, Vivian J.

doi:10.1016/j.ydbio.2020.06.013

Cited by 20 publications

(28 citation statements)

References 165 publications

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“…Here we describe the case of a female infant presenting with the typical clinical features of OFCD syndrome. OFCD remains a rare genetic pathological syndrome with no more than 100 cases reported to date [ 6 ]. We have summarized the OFCD cases published in recent 5 years (Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

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A novel deletion mutation in the BCOR gene is associated with oculo-facio-cardio-dental syndrome: a case report

Mai

Xiang

et al. 2022

BMC Pediatr

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Background Oculo-facio-cardio-dental syndrome is a rare X-linked dominant syndrome, characterized by radiculomegaly, congenital cataracts, dysmorphic facial features, and congenital heart disease. Because of the rarity, this syndrome could be misdiagnosed by the clinician, especially for the infant who may present only one to two systems involved. Case presentation Here we report a 3-month-old female infant presenting with typical clinical manifestations of oculo-facio-cardio-dental syndrome, like ocular, facial, cardiac, and skeletal abnormalities, and the genetic analyses of the proband and her parents were provided. Genetic evaluations were completed using whole exon sequencing, which revealed a novel heterozygous mutation between exons 7 and 14 of the BCOR gene(OMIM:300485) in this patient but not in her parents. This mutation is likely to encode a premature stop codon producing a truncated protein. Our patient was diagnosed early enough to allow for the cardiac defects to be treated first, and she will be closely followed up to ensure that any new presentations are treated in a timeous manner. Conclusion This patient fits the diagnostic criteria for oculo-facio-cardio-dental syndrome and is the youngest oculo-facio-cardio-dental syndrome patient ever reported, which is most important for her prognosis. In addition, this manuscript also describes a novel potenitally causative mutation for this syndrome.

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Section: Discussionmentioning

confidence: 99%

“…BCOR plays a central role in maintaining pluripotency, inducing differentiation and determining cell fate [ 4 ], and the BCOR protein is widely expressed in various human tissues. This means that BCOR is of clinical interest for its important roles in development [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

A novel deletion mutation in the BCOR gene is associated with oculo-facio-cardio-dental syndrome: a case report

Mai

Xiang

et al. 2022

BMC Pediatr

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“…Several X-linked genes are possible candidates for mediating autosomal replication timing delays. For instance, ELK1 is an X-linked transcription factor primarily expressed in placenta and ovarian tissue (Uhlen et al, 2015) that was shown to cause transcriptional changes of autosomal genes in reactivated-X ESCs (Bruck et al, 2013); PPP2R3B encodes a protein phosphatase 2A subunit that delays the firing of replication origins throughout the genome by stabilizing the Cdc6-Cdt1 interaction (van Kempen et al, 2016); BCOR, a Polycomb-group repressive complex gene, is required for normal placental development (Hamline et al, 2020); and NAP1L2, which encodes a nucleosome assembly protein, is induced during differentiation of mouse trophoblast stem cells to TGCs (Attia et al, 2007) and is upregulated in human haploid ESCs (Sagi et al, 2016). The role of these and other genes in haploid replication delays could be tested by knockout, knockdown or overexpression in haploid and diploid ESCs.…”

Section: Discussionmentioning

confidence: 99%

Delayed DNA replication in haploid human embryonic stem cells

Edwards

Zuccaro

Sagi

et al. 2021

Preprint

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Haploid human embryonic stem cells (ESCs) provide a powerful genetic system but diploidize at high rates. We hypothesized that diploidization results from aberrant DNA replication. To test this, we profiled DNA replication timing in isogenic haploid and diploid ESCs. The greatest difference was the earlier replication of the X chromosome in haploids, consistent with the lack of X chromosome inactivation. Surprisingly, we also identified 21 autosomal regions that had dramatically delayed replication in haploids, extending beyond the normal S phase and into G2/M. Haploid-delays comprised a unique set of quiescent genomic regions that are also under-replicated in polyploid placental cells. The same delays were observed in female ESCs with two active X chromosomes, suggesting that increased X chromosome dosage may cause delayed autosomal replication. We propose that incomplete replication at the onset of mitosis could prevent cell division and result in re-entry into the cell cycle and whole genome duplication.

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“…To investigate the functional relevance of a C-terminal deletion of BCOR during GNP development and tumorigenesis, we used a genetically engineered mouse strain to generate Cre inducible excision of Bcor exons 9 and 10 in Atoh1-positive GNPs (Bcor ΔE9-10 ) (Fig. 1K; Hamline et al 2020). At the protein level, this excision results in reduced expression of a truncated BCOR protein (Fig.…”

Section: Bcor Is Expressed In Proliferating Murine Gnpsmentioning

confidence: 99%

“…Bcor conditional knockout mice were generated by breeding of Bcor fl/fl (loxP sites flanking exons 9 and 10) (Hamline et al 2020) with Atoh1-Cre (JAX 011104) and Ptch1 heterozygous mice (Goodrich et al 1997). Genotyping primer sequences are available in Supplemental Table S5.…”

Section: Animalsmentioning

confidence: 99%

Functional loss of a noncanonical BCOR–PRC1.1 complex accelerates SHH-driven medulloblastoma formation

Kutscher¹,

Okonechnikov²,

Batora³

et al. 2020

Genes Dev.

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Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (Bcor ΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCOR ΔE9-10 ). While Bcor ΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, Bcor ΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1 +/− ;Bcor ΔE9-10 tumors, the growth factor gene Igf2 was aberrantly upregulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1 +/− GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1 +/− ;Bcor ΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

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OFCD syndrome and extraembryonic defects are revealed by conditional mutation of the Polycomb-group repressive complex 1.1 (PRC1.1) gene BCOR

Cited by 20 publications

References 165 publications

A novel deletion mutation in the BCOR gene is associated with oculo-facio-cardio-dental syndrome: a case report

A novel deletion mutation in the BCOR gene is associated with oculo-facio-cardio-dental syndrome: a case report

Delayed DNA replication in haploid human embryonic stem cells

Functional loss of a noncanonical BCOR–PRC1.1 complex accelerates SHH-driven medulloblastoma formation

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