MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

Abstract

Rett syndrome (RTT) is a progressive neurodevelopmental disorder that is caused by mutations in the X-linked methyl-CpG-binding protein2 (MECP2) gene. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. The p. T158M mutation (15.7%) was the most common, followed in order of frequency by p. R168X (11.8%), p. R133C (6.9%), p. R270X (6.9%), p. G269fs (6.9%), p. R255X (4.9%), and p. R306C (3.9%). In addition, we identified five novel MECP2 mutations: three missense (p. K305E, p. V122M, p. A358T), one insertion (c.45-46ins-GGAGGA), and one 22 bp deletion (c.881-902del22). Large deletions represented 10.5% of all identified MECP2 mutations. Conversely, mutations in exon 1 appeared to be rare (0.9%). The remaining cases without MECP2 mutations were screened for the cyclin-dependent kinase-like 5 (CDKL5) gene using denaturing high-performance liquid chromatography (DHPLC). One synonymous mutation (p. I72I) was found in exon 5, suggesting that CDKL5 is a rare cause of RTT. The overall MECP2 mutation detection rate for this patient series was 84.3:87.9% in 107 classical RTT cases and 57.1% in 14 atypical RTT cases. Moreover, there were two patients with homozygous mutations and normal female karyotypes. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases.

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

“…Indeed, the p.Ile72Thr mutation of patient 2 is the third affecting Ile72 to be discovered. A different change (p.Ile72Asn) was reported by Evans [21] and a silent change (p.Ile72Ile) was observed in a Chinese Rett cohort [4] and has so far been excluded as a polymorphism.…”

“…Following the description of two girls with West syndrome (OMIM#308350) carrying X;autosome translocations disrupting the cyclin-dependent kinase-like 5 gene (CDKL5; OMIM#300203) [1], other mutations within the same gene have been reported in patients manifesting a similar clinical picture, thus indicating that the associated phenotype is characterised by early-onset untreatable seizures, infantile spasms, severe mental retardation and some features of Rett syndrome (RTT: OMIM#312750) [2][3][4][5][6]. On the basis of this clinical presentation, the CDKL5-positive group has been assimilated to the Hanefeld early seizure variant of RTT [2].…”

The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1

“…The second alteration, Ala370Thr, was identified in a singleton family of African ancestry and previously reported in three Chinese individuals: one female with Rett syndrome, her unaffected mother and a male presenting with epileptic encephalopathy [Fig. C; Li, Pan, Bao, Zhang, & Wu, ; Wong & Li, ]. Both of these alterations must be further evaluated to isolate their potential functional consequences.…”

Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression

“…Besides the classical form, several variant forms such as mental retardation with spasticity, congenital hypotonia with infantile spasms or severe neonatal encephalopathy in males have been delineated. Although in about 90% of patients with classical Rett syndrome mutations or deletions of the X-linked MECP2 gene were detectable, less than 50% of atypical patients showed MECP2 defects [Fukuda et al, 2005;Kammoun et al, 2004;Li et al, 2007;Zahorakova et al, 2007]. Few of the MECP2 negative patients were recently shown to suffer from CDKL5 [Archer et al, 2006;Weaving et al, 2004] or FOXG1 [Ariani et al, 2008;Mencarelli et al, 2010;Philippe et al, 2010] mutations.…”