A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

Guen, Tangui Le; Fichou, Yann; Nectoux, Juliette; Bahi‐Buisson, Nadia; Rivier, François; Boddaert, Nathalie; Diebold, Bertrand; Héron, Delphine; Chelly, Jamel; Bienvenu, Thierry

doi:10.1002/humu.21422

Cited by 18 publications

(25 citation statements)

References 20 publications

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“…Our male patient carries a de novo p.Ala193Thr missense mutation. To date, only 3 missense mutations in FOXG1 have been reported [Mencarelli et al, 2010;Le Guen, 2011b]. Interestingly, all 4 missense mutations, including the one identified in our patient, are located within the highly conserved DNA-binding forkhead domain of the protein (amino acids 181-275).…”

Section: Discussionmentioning

confidence: 88%

Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome

Bergh²,

Ponomarenko³

et al. 2010

Mol Syndromol

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We screened a cohort of 5 male and 20 female patients with a Rett spectrum disorder for mutations in the coding region of FOXG1, previously shown to cause the congenital variant of Rett syndrome. Two de novo mutations were identified. The first was a novel missense mutation, p.Ala193Thr (c.577G>A), in a male patient with congenital Rett syndrome, and the second was the p.Glu154GlyfsX301 (c.460dupG) truncating mutation in a female with classical Rett syndrome, a mutation that was previously reported in an independent patient. The overall rate of FOXG1 mutations in our cohort is 8%. Our findings stress the importance of FOXG1 analysis in male patients with Rett syndrome and in female patients when mutations in the MECP2 and CDKL5 genes have been excluded.

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Section: Discussionmentioning

confidence: 88%

Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome

Bergh²,

Ponomarenko³

et al. 2010

Mol Syndromol

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“…Including this study, 26 point mutations, 25 CNVs, and 2 t(2;14) balanced translocations have been reported in patients with a FOXG1-related phenotype. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][17][18][19][20][21][22] The male-to-female ratios is 7/26 (27%) for point mutations and 13/25 (52%) for CNVs. The preponderance of females in patients positive for a FOXG1 point mutation is most probably due to the initial description of FOXG1 deleterious alleles in females with congenital RTTs.…”

Section: Discussionmentioning

confidence: 99%

“…Point mutations in the Forkhead box G1 (FOXG1) gene, encoding a brain-specific transcriptional repressor essential for the development of the telencephalon, were found to be responsible for congenital [1][2][3][4][5][6][7] or classical 2,5 Rett syndrome (RTT) in females and also in males. [5][6][7] Copy number variations (CNV) in 14q12 containing the FOXG1 gene have been identified in both genders in patients suffering from neurodevelopmental disorders.…”

Section: Introductionmentioning

confidence: 99%

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

et al. 2012

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The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly ( À4 to À6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.

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“…17 Philippe et al, 25 Le Guen et al, 24,35 Mencarelli et al, 15 Bahi-Buisson et al, 16 Takahashi et al 26 …”

Section: Chromosomal Microarray Analysis Methodsunclassified

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

Ellaway

Bettella

et al. 2012

Eur J Hum Genet

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Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in B90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.

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A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

Cited by 18 publications

References 20 publications

Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome

Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

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