FOXG1 mutations in Japanese patients with the congenital variant of Rett syndrome

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by microcephaly, psychomotor regression, seizures and stereotypical hand movements. Recently, deletions and inactivating mutations in FOXG1, encoding a brain-specific transcription factor that is critical for forebrain development, have been found to be associated with the congenital variant of RTT. Here we report the clinical features and molecular characteristics of two cases of the congenital variant of RTT. We conducted mutation screenings of FOXG1 in a cohort of 15 Japanese patients with a clinical diagnosis of atypical RTT but without MECP2 and CDKL5 mutations. Two unrelated female patients had heterozygous mutations (c.256dupC, p.Gln86ProfsX35 and c.689G>A, pArg230His). Both showed neurological symptoms from the neonatal period, including hypotonia, irritability and severe microcephaly. Further, their psychomotor development was severely impaired, as indicated by their inability to sit unaided or acquire speech sounds, and they had a hyperkinetic movement disorder, because both displayed hand stereotypies and jerky movements of the upper limbs. Brain magnetic resonance imaging scans revealed delayed myelination with hypoplasia of the corpus callosum and frontal lobe. These cases confirm the involvement of FOXG1 in the molecular etiology of the congenital variant of RTT and show the characteristic features of FOXG1-related disorder.

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

“…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.…”

“…[5][6]17 The same c.256dupC frameshift has already been reported twice in patients with congenital RTT. 7,18 The c.256del/dup is the second mutational hot spot affecting a mononucleotide repeat in FOXG1. We also describe five new CNVs in 14q12 in two males and three females.…”

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

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

“…The mutation has been previously identified in both a female and a male with congenital variant of Rett syndrome. 24,26 Screening of the same 32 patients did not reveal any pathogenic mutations in PRKD1, a protein kinase involved in extracellular receptor-mediated signal transduction pathways. A number of known nonpathogenic polymorphisms were identified and shown in Table 2.…”

Neonatal MeCP2 is important for the organization of sex differences in vasopressin expression

“…NF-L is a neuron-specific cytoskeletal gene, 30 and Foxg1 is a gene that encodes for a transcription factor that is important for brain development and has been recently identified to be deleted or inactivated in Rett syndrome. 31,32 MeCP2 mRNA was also assessed in order to ensure that expression levels returned to normal two weeks following the infusions on PN0-2, as previously shown in reference 14. There was no effect of neonatal MeCP2 siRNA on the expression of any of these genes.…”