Rare dental abnormalities seen in oculo-facio-cardio-dental (OFCD) syndrome: three new cases and review of nine patients

Schulze, Birgit R. B.; Horn, Denise; Kobelt, Albrecht; Tariverdian, Gholamali; Stellzig, Angelika

doi:10.1002/(sici)1096-8628(19990219)82:5<429::aid-ajmg13>3.0.co;2-s

Cited by 43 publications

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“…There is very strong expression of Bcor in extraembryonic tissue. Expression of Bcor in the developing eye, tooth primordium, limb buds, branchial arches and multiple nervous system tissues also distinctly correlates with many of the tissues adversely affected in OFCD and LM patients (Ng et al, 2004;Schulze et al, 1999). This analysis provides important information for the analysis of future mouse models of OFCD.…”

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confidence: 80%

“…OFCD is the primary subtype of OMIM #300166 microphthalmia, syndromic 2 (MCOPS2) and is characterized by ocular, dental, cardiac and digital anomalies in heterozygous females (Ng et al, 2004;Schulze et al, 1999). Males with OFCD do not survive due to presumed embryonic lethality (Ng et al, 2004).…”

Section: )mentioning

confidence: 99%

“…Males with OFCD do not survive due to presumed embryonic lethality (Ng et al, 2004). Since BCOR lies on the X chromosome in both mice and humans, random X-inactivation results in mosaic expression of the mutant allele contributing to varying disease severity in females (Ng et al, 2004;Schulze et al, 1999). Additionally, peripheral leukocytes of female patients show preferential survival of cells in which the mutant allele of BCOR lies on the inactivated X chromosome, indicating a strong requirement for BCOR in hematopoiesis (Hedera and Gorski, 2003;Ng et al, 2004).…”

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confidence: 99%

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Characterization of Bcor expression in mouse development

Wamstad

Bardwell

2007

Gene Expression Patterns

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Mutation of the gene encoding the transcriptional corepressor BCOR results in the X-linked disorder Oculofaciocardiodental Syndrome (OFCD or MCOPS2). Female OFCD patients suffer from severe ocular, craniofacial, cardiac and digital developmental defects and males do not survive through gestation. BCOR can mediate transcriptional repression by the oncoprotein BCL6 and has the ability to reduce transcriptional activation by AF9, a known mixed-lineage leukemia (MLL) fusion partner. The essential role of BCOR in development and its ability to modulate activity of known oncogenic proteins prompted us to determine the expression profile of Bcor during mouse development. Identification of independently transcribed exons in the 5′ untranslated region of Bcor suggests that three independent promoters control the expression of Bcor in mice. Although Bcor is widely expressed in adult mouse tissues, analysis of known spliced isoforms in the coding region of Bcor reveals differential isoform usage. Whole mount in situ hybridization of mouse embryos shows that Bcor is strongly expressed in the extraembryonic tissue during gastrulation and expression significantly increases throughout the embryo after embryonic turning. During organogenesis and fetal stages Bcor is differentially expressed in multiple tissue lineages, with a notable presence in the developing nervous system. Strikingly, we observed that Bcor expression in the eye, brain, neural tube and branchial arches correlates with tissues affected in OFCD patients.

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confidence: 80%

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confidence: 99%

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confidence: 99%

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Characterization of Bcor expression in mouse development

Wamstad

Bardwell

2007

Gene Expression Patterns

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“…OFCD [6][7][8][9][10] is a distinct form of syndromic microphthalmia with congenital cataracts, narrow face, broad nasal tip with separated cartilage, cleft palate, and cardiac and dental anomalies (canine radiculomegaly, root dilacerations, oligodontia and retained deciduous teeth; Fig. 2).…”

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“…7 Genetics Division, Children's National Medical Center, Washington, DC, USA. 8 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. 9 Department of Medical Genetics, University Medical Centre Utrecht, Postbus 85090, 3508 AB Utrecht, the Netherlands.…”

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Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR

et al. 2004

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Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C→T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR 4 ) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus 3 . Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCDmutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.We had previously localized MAA2 to a 10-Mb candidate region of Xp 3 . To identify the gene, we narrowed this region by excluding regions deleted in males with Xp deletions but without microphthalmia. Coriell cell line GM07947 is from a male with Duchenne muscular dystrophy, chronic granulomatous disease, McLeod phenotype and retinitis pigmentosa without microphthalmia 5 . Sequence-tagged site (STS) mapping confirmed previous data and oriented it to current genome maps. The deletion extended from DMD (telomeric) to between RPGR and OTC (centromeric; Fig. 1). The Coriell cell line GM10283 excluded two genes telomeric to DMD. This narrowed the critical region to ∼5 Mb, including 12 identified genes not known to be mutated in humans. One of these, DDX3, has an active Y homolog, and we therefore considered it unlikely to underlie a disorder with X-linked recessive inheritance. We sequenced the remaining 11 genes in members of the family in which MAA2 was originally identified. Ten of these genes showed no alterations, but we identified a missense change (nt 254C→T) in BCOR 4 that co-segregated with the disease phenotype (lod score of 2.46, above the threshold of 2.0 for X linkage 3 ). The corresponding residue of human BCOR, Pro85, is conserved in mouse, rat, chicken and pufferfish (Fig. 2), and we did not detect the nt 254C→T mutation among >450 control chromosomes. X-inactivation studies of peripheral blood leukocytes in two carriers of the mutation showed no ske...

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Oculo‐facio‐cardio‐dental syndrome: Skewed X chromosome inactivation in mother and daughter suggest X‐linked dominant Inheritance

Hedera

Gorski

2003

American J of Med Genetics Pt A

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Oculo-facio-cardio-dental syndrome (OFCD) is an uncommon multiple congenital anomaly syndrome that is characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects, and dental anomalies including canine radiculomegaly and oligodontia. Although most cases of OFCD are sporadic, since all reported OFCD individuals have been female, it has been suggested that OFCD is an X-linked dominant trait. Here we report two affected female patients with OFCD, a mother and daughter, who both had congenital cataracts, microphthalmia, characteristic dental anomalies, and typical facial dysmorphisms. These features were diagnostic for OFCD; thus, these cases represent the second documented instance of mother-to-daughter OFCD transmission. In addition to the clinical features typically seen in OFCD individuals, the affected daughter exhibited several additional congenital anomalies including intestinal malrotation and hypoplastic thumbs. Thus, these cases further define and expand the OFCD clinical phenotype. These two individuals also displayed a skewed pattern of X chromosome inactivation. Together, these data strongly support the hypothesis that OFCD is inherited as an X-linked dominant condition.

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Rare dental abnormalities seen in oculo-facio-cardio-dental (OFCD) syndrome: three new cases and review of nine patients

Cited by 43 publications

References 9 publications

Characterization of Bcor expression in mouse development

Characterization of Bcor expression in mouse development

Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR

Oculo‐facio‐cardio‐dental syndrome: Skewed X chromosome inactivation in mother and daughter suggest X‐linked dominant Inheritance

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