FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome

Ariani, Francesca; Hayek, Joussef; Rondinella, Dalila; Artuso, Rosangela; Mencarelli, Maria Antonietta; Spanhol-Rosseto, Ariele; Pollazzon, Marzia; Buoni, Sabrina; Spiga, Ottavia; Ricciardi, Sara; Meloni, Ilaria; Longo, Ilaria; Mari, Francesca; Broccoli, Vania; Zappella, Michele; Renieri, Alessandra

doi:10.1016/j.ajhg.2008.05.015

Cited by 374 publications

(373 citation statements)

References 26 publications

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“…32 In addition, overlapping expression of FOXG1 and MECP2 has been demonstrated in differentiating forebrain cortex. 17 FoxG1 is hypothesised to protect Figure 2 Expression of PRKD1 and FOXG1 in 14q12 microdeletion patients. Folds of expression, relative to two normal controls, of FOXG1 (white bars) and PRKD1 (black bars) in the three patients were measured in a lymphoblast cell line for case 1 and in whole blood from cases 2 and 3.…”

Section: Discussionmentioning

confidence: 99%

“…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

“…7,8,[12][13][14] Mutation analyses have identified de novo loss-of-function point mutations in FOXG1, particularly in patients with the congenital form of Rett syndrome. [15][16][17] Duplications of FOXG1 are also found in patients with epilepsy and intellectual impairment, [18][19][20][21] highlighting the importance of gene dosage at this locus, although more recently the pathogenicity of FOXG1 duplications has been questioned. 22 We report the clinical features and array CGH findings of three atypical Rett syndrome patients.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…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

Section: Introductionmentioning

confidence: 99%

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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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“…Previously, we had reported a similarly affected patient with a deletion that also included FOXG1, 2 and more recently three patients with West syndrome were reported to have duplications that included FOXG1. 3,4 FOXG1 encodes a brainspecific transcriptional repressor, 5 and deletions and point mutations in FOXG1 are known to cause the congenital variant of Rett syndrome, 6 making duplication of FOXG1 a strong candidate for the neurocognitive impairment in patient with 14q12 duplications.…”

mentioning

confidence: 99%

“…Neither the son nor the father exhibited mental retardation or epilepsy. They also identified an B3 Mb duplication of the 14q12 region, including FOXG1, in a child enrolled as a control subject in the CHOP CNV database 6 and questioned the pathogenicity of FOXG1 duplication.…”

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confidence: 99%

Questionable pathogenicity of FOXG1 duplication

et al. 2012

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Forkhead Transcription Factors in Genetic Disease

Baetens

Verdin

Cools

2013

Encyclopedia of Life Sciences

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Forkhead transcription factors represent an important family of proteins, for which more than 2000 family members have been identified so far, 26 of which can be found in humans. FOX genes exhibit many important functions in both development and adult life. Therefore, it is not surprising that alterations in these genes can cause of a broad range of developmental diseases and cancer. Today, 13 FOX genes are associated with developmental disorders. Mutations in five of them ( FOXC1 , FOXC2 , FOXD3 , FOXE3 and FOXL2 ) lead to an ocular phenotype, while mutations in three genes ( FOXG1 , FOXP1 and FOXP2 ) are a known cause for neurodevelopmental disorders, mutations in two ( FOXL2 and FOXO3A ) are associated with premature ovarian failure and mutation in other two genes ( FOXN1 and FOXP3 ) are involved in immunodeficiency syndromes. Finally, FOXF1 mutations cause a lung development disorder. In this article, the different developmental disorders caused by mutations in FOX genes are reviewed. In addition, the article briefly touches cancers caused by genetic defects in FOX genes. Key Concepts: Forkhead transcription factor genes represent an important gene family, consisting out of more than 2000 members. In human, 26 family members have been identified and there are 8 FOX gene clusters. The forkhead domain is built up by three α‐helices, two β‐sheets and two loops. These loops resemble wings of a butterfly, giving the family its nickname: winged helix transcription factors. Forkhead transcription factors play important roles in a wide range of signalling pathways. Mutations in FOX genes are known to cause hereditary developmental disorders. Five mutated FOX genes are associated with an ocular phenotype. Forkhead transcription factors are also involved in cancer and ageing.

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FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome

Cited by 374 publications

References 26 publications

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

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

Questionable pathogenicity of FOXG1 duplication

Forkhead Transcription Factors in Genetic Disease

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