Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome

Gauthier, Julie; Amorim, Giovana de; Mnatzakanian, Gevork N.; Saunders, Carol J.; Vincent, John B.; Toupin, Sylvie; Kauffman, David; St‐Onge, Judith; Laurent, Sandra B.; MacLeod, Patrick; Minassian, Berge A.; Rouleau, Guy A.

doi:10.1017/s0317167100004200

Cited by 6 publications

(7 citation statements)

References 20 publications

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“…In Patient 1, we detected a novel mutation, c.1A > T that disrupts the initiation codon, changing it to a leucine. We reported on the identification of this mutation previously [Gauthier et al, 2005]. In silico analysis of translation initiation using NetStart predicts that translation of MeCP2_e1 would be ablated, but without any negative affect on translation of MeCP2_e2.…”

Section: Resultsmentioning

confidence: 95%

“…All mutations localized to exon 1 reported until recently have been either small insertions or deletions or large deletions removing the entire exon. These three single base pair changes are the first point mutations to be reported in exon 1 of the MECP2 gene [also see Gauthier et al, 2005]. The c.1A > T and c.1A > G mutations alter the initiation codon, which would mostly likely result in absent translation of MeCP2_e1.…”

Section: Discussionmentioning

confidence: 97%

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Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome

Saunders

Minassian

Chow

et al. 2009

American J of Med Genetics Pt A

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. Recently, a new MeCP2 isoform was described, MeCP2_e1, which skips exon 2 and has an alternative N-terminus, translated from exon 1, whereas MeCP2_e2 is translated from a start codon in exon 2. Since the incorporation of exon 1 into standard sequencing protocols for RTT, few exon 1 mutations have been described and are thus assumed to be only rare causes of RTT. Also, studies have suggested that the frameshift mutations identified in exon 1 affect both isoforms. Our aim in this study was to assess the frequency of mutations in exon 1, their relationship to phenotype, and the implications on the etiological role for the isoform MeCP2_e1 in RTT, versus the previously described isoform, MeCP2_e2. We sequenced MECP2 in 51 females with various clinical presentations, including developmental delay, autism, atypical and classical RTT, referred to our laboratories for testing. In patients with identified mutations, X-chromosome inactivation was analyzed. We identified four patients with exon 1 mutations; three were novel (c.1A > T; c.1A > G; c.5C > T), two of which affected the start codon, one a missense change, and one patient had a previously reported splice site mutation, c.62 + 1delGT. The four patients fit criteria for classical RTT, and thus these findings add support to previous reports that exon 1 mutations may be associated with a severe phenotype. Also, these findings add significant weight to the mounting evidence suggesting that the MeCP2_e1 isoform is the etiologically relevant form of the protein.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome

Saunders

Minassian

Chow

et al. 2009

American J of Med Genetics Pt A

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“…However, subsequently, several classic Rett patients were identified with mutations affecting the start codon in exon 1 (Gauthier et al, 2005;Saunders et al, 2009). Levels of mRNA for MeCP2-E1 and E2 were unaffected, and peripheral blood lymphocytes were still positive for MeCP2 antibodies, and thus presumably only able to generate the MeCP2-E2 protein (Gianakopoulos et al, 2012).…”

Section: Mecp2 N-terminal Mutationsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

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“…Autism is a neurodevelopmental disorder characterized by deficits in communication and reciprocal social interaction accompanied by repetitive/stereotyped behaviors and/or restricted areas of interest. Autism disproportionately affects males, and some researchers have therefore searched for the involvement of X‐linked loci [Jamain et al, 2003; Gauthier et al, 2005; Gong et al, 2008], including searches for MECP2 mutations in cases of idiopathic autism [Lam et al, 2000; Vourc'h et al, 2001; Beyer et al, 2002; Carney et al, 2003; Lobo‐Menendez et al, 2003; Coutinho et al, 2007]. These studies demonstrated that mutations in the coding region of MECP2 are a rare cause of idiopathic autism.…”

Section: Autism and Mecp2 Duplication Syndromementioning

confidence: 99%

The MECP2 duplication syndrome

Ramocki

Tavyev

Peters

2010

American J of Med Genetics Pt A

292

306

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In this review, we detail the history, molecular diagnosis, epidemiology, and clinical features of the MECP2 duplication syndrome, including considerations for the care of patients with this Xlinked neurodevelopmental disorder. MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation, autism or autistic features, poor speech development, recurrent infections, epilepsy, progressive spasticity, and, in some cases, developmental regression. Most of the reported cases are inherited, however, de novo cases have been documented. While carrier females have been reported to be unaffected, more recent research demonstrates that despite normal intelligence, female carriers display a range of neuropsychiatric phenotypes that pre-date the birth of an affected son. Given what we know of the syndrome to date, we propose that genetic testing is warranted in cases of males with infantile hypotonia and in cases of boys with mental retardation and autistic features with or without recurrent infections, progressive spasticity, epilepsy, or developmental regression. We discuss recommendations for clinical management and surveillance as well as the need for further clinical, genotype-phenotype, and molecular studies to assist the patients and their families who are affected by this syndrome.

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Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome

Cited by 6 publications

References 20 publications

Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome

Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

The MECP2 duplication syndrome

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