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

  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},
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… 

The impact of CFNS-causing EFNB1 mutations on ephrin-B1 function

Pathogenic mechanisms in CFNS manifestation include impaired ephrin-B1 signalling combined with cellular interference, and missense mutations located in the extracellular ephrine domain involved in Eph-ephrin-B 1 recognition and higher order complex formation are studied.

Clinical and molecular characterization of craniofrontonasal syndrome: new symptoms and novel pathogenic variants in the EFNB1 gene

The primary finding was the description of monozygotic twins, i.e., patients 5 and 6, discordant for the CFNS phenotype, which pointed to an unusual phenomenon of mildly affected females with CFNS, who may not manifest features suggestive of the syndrome.

A Novel de Novo Mutation Within EFNB1 Gene in a Young Girl with Craniofrontonasal Syndrome

A novel de novo missense mutation 373G>A was identified within the EFNB1 gene, leading to the replacement of glutamic acid at amino acid position 125 with lysine, which is expected to disrupt the interaction between the Eph receptor and ephrin B1 ligand, thus leading to craniofrontonasal syndrome.

The First Description of Monozygotic Twin Females Discordant for the Craniofrontonasal Syndrome Phenotype and the Report of Four Novel Pathogenic Variants in the EFNB1 Gene

The description of monozygotic twin patients 5 & 6 harbouring an identical p.(Glu210*) variant located in the EFNB1 gene pointed to an unusual phenomenon of mildly affected females with CFNS, who may not manifest features suggestive of the syndrome.

Four novel mutations in EFNB1 in Indian patients with craniofrontonasal syndrome

Although patients 3 and 4 showed the most severe facial dysmorphism and syndactyly, there were no structural CNS changes or developmental delay, and the absence of an obvious correlation between mutation type, severity, and expression of symptoms is illustrated.

Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1

Patients with EFNB1 mutations have a clear phenotype and this study will facilitate genetic counseling of parents and patients, and contribute to the diagnostic and screening process of patients with suspected CFNS.

A Novel De Novo EFNB1 Gene Mutation in a Mexican Patient with Craniofrontonasal Syndrome

The clinical and molecular studies of a female subject with CFNS are described and a novel de novo c.473T>C (p.M158T) mutation in exon 3 of EFNB1 was demonstrated in this patient, expanding the mutational spectrum exposed by CNFS.

Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

It is found that EPHRIN-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape, which advances the understanding of the etiology and signaling interactions underlying CFNS dysmorphology.

Use of targeted next‐generation sequencing for molecular diagnosis of craniosynostosis: Identification of a novel de novo mutation of EFNB1

This study performed targeted, massively parallel sequencing using a next‐generation sequencer, and identified a novel EFNB1 mutation, c.270_271delCA, in a Japanese female patient with craniosynostosis, determined to be de novo in origin.



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

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.

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)

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

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

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
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

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.

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

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.