Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic

@article{Wieland2008DissectingTM,
  title={Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic},
  author={Ilse Wieland and Roman Makarov and William Reardon and Sigrid Tinschert and Alice Goldenberg and Patrick Thierry and Peter F Wieacker},
  journal={European Journal of Human Genetics},
  year={2008},
  volume={16},
  pages={184-191}
}
Craniofrontonasal syndrome (CFNS) is an X-linked malformation syndrome with variable phenotype that is caused by mutations in the ephrin-B1 gene (EFNB1). Over 50% of EFNB1 mutations result in premature termination codons that may elicit mRNA degradation by the nonsense-mediated decay pathway. To assess the effects of various mutations at the transcript level, expression of EFNB1 mRNA was studied by RT-PCR in fibroblast cultures established from CFNS female patients. Compared to the wild-type… 

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References

SHOWING 1-10 OF 28 REFERENCES

The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males.

TLDR
It is concluded that the major factor accounting for the relative scarcity of carrier males is the bias toward mutations in the paternal germline combined with reduced reproductive fitness in affected females.

Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.

TLDR
It is concluded that mutations in EFNB1 cause CFNS, a X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations whereas the genetic defect causes no or only mild abnormalities in male carriers.

Twenty‐six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS)

TLDR
It is concluded that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor‐ligand interaction, oligomerization, and ephrin‐B1 reverse signaling.

Contiguous gene deletions involving EFNB1, OPHN1, PJA1 and EDA in patients with craniofrontonasal syndrome

TLDR
Although it is too early to predict the future cognitive performance of the two infant patients with contiguous gene deletions of OPHN1–EFNB1–PJA1, mild learning disabilities have been recognized in the older, third patient.

A Novel Mutation in EFNB1, Probably with a Dominant Negative Effect, Underlying Craniofrontonasal Syndrome

TLDR
A Thai woman with CFNS is reported, in whom a novel mutation was discovered: c.685_686insG, in exon 5 of EFNB1, which is the first insertion and the most 3′ point mutation inEFNB1 reported to date.

Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome.

  • S. TwiggR. Kan A. Wilkie
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2004
TLDR
It is proposed that in heterozygous females, patchwork loss of ephrin-B1 disturbs tissue boundary formation at the developing coronal suture, whereas in males deficient in ephin-B 1, an alternative mechanism maintains the normal boundary.

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

TLDR
It is reported that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway.

A novel phenotypic pattern in X-linked inheritance: craniofrontonasal syndrome maps to Xp22.

TLDR
Data is reported confirming that CFNS is X-linked, mapping to a 13 cM interval in Xp22 with a maximum two-point lod score of 3.9 and detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X- linked disorder.

Isolation of DICE1: A gene frequently affected by LOH and downregulated in lung carcinomas

TLDR
The location of the DICE1 gene in the region of allelic loss, its high evolutionary conservation and the downregulation of expression in carcinoma cells suggests that DICE 1 is a candidate tumor suppressor gene in non-small cell lung carcinomas and possibly in other sporadic carcinomas.