Rett syndrome is caused by mutations in the gene MECP2 in ∼80% of affected individuals. We describe a previously unknown MeCP2 isoform. Mutations unique to this isoform and the absence, until now, of identified mutations specific to the previously recognized protein indicate an important role for the newly discovered molecule in the pathogenesis of Rett syndrome.Rett syndrome (RTT; OMIM 312750) is characterized by onset, in girls, of a gradual slowing of neurodevelopment in the second half of the first year of life that proceeds towards stagnation by age 4 years, followed by regression and loss of acquired fine motor and communication skills. A pseudostationary period follows during which a picture of preserved ambulation, aberrant communication and stereotypic hand wringing approximates early autism. Regression, however, remains insidiously ongoing and ultimately results in profound mental retardation 1 .Up to 80% of individuals with RTT have mutations 2,3 in exons 3 and 4 of the four-exon gene MECP2 (Fig. 1a) 4 encoding the transcriptional repressor MeCP2. In the known transcript of the gene, all four exons are used, the translation start site is in exon 2, and exon 1 and most of exon 2 form the 5′ untranslated region (UTR) 4 . For clarity, we refer to this transcript as MECP2A and its encoded protein as MeCP2A. We sought to identify MECP2 splice variants contributing new coding sequence that might contain mutations in the remaining individuals with RTT. Inspection of the 5′ UTR showed that, whereas exon 2 has a number of in-frame stop codons upstream of the ATG start codon, exon 1 contains an open reading frame across its entire length, including an ATG. Submitting a theoretical construct composed of exons 1, 3 and 4 to the ATGpr program (http://www.hri.co.jp/atgpr/), which predicts the likelihood that an ATG will be an initiation codon based on the significance of its surrounding Kozak nucleotide context, returned a reliability score of 97%, as compared with 64% for MECP2A. A search in EST databases identified eight examples of our theorized transcript, which we named MECP2B (Fig. 1b), as compared with 14 examples of MECP2A. MECP2B is predicted to encode a new isoform, MeCP2B, with an alternative, longer N terminus determined by exon 1 (see Supplementary Table 1 online).To confirm that MECP2B is expressed and not merely an artifact of cDNA library preparation, we amplified cDNA by PCR from a variety of tissues using a 5′ primer in exon 1 and a 3′ primer in exon 3 (Fig. 1a). We obtained two PCR products corresponding in size and sequence to MECP2A and MECP2B in all tissues, including fetal and adult brain and different brain subregions (Fig. 1c). Results in mouse were similar (Fig. 1c). We quantified the expression levels of the two transcripts in adult human brain. Expression of MECP2B was ten times higher than that of MECP2A (Fig. 1d). We studied the subcellular localization of MeCP2B after transfection of 3′ myc-tagged MECP2B into COS-7 cells and found it to be principally in the nucleus (Fig. 1e).To deter...

Given the limitations of allograft biopsy, our pilot study suggests the potential for magnetic resonance elastography as a novel noninvasive measure of whole-allograft fibrosis burden that may predict future changes in kidney function. Future studies exploring the utility and accuracy of magnetic resonance elastography are needed.

A new splice variant of the Rett syndrome gene, MECP2, was recently identified, that includes coding sequence from exon 1, and is the predominant transcript in the central nervous system. This sequence encodes polyalanine and polyglycine stretches within the N-terminal portion of MeCP2, and may confer novel functional properties to the protein. We screened autism, mental retardation (MR), and control populations for sequence variation within this region, and identified variation in approximately 1% of MR cases screened (N = 1,410). No variants were identified in the autism sample (N = 401). Most of these variants occur within a trinucleotide repeat region and result in change in number of alanine or glycine residues within the repeat stretches. We suggest some of these variants may be a relatively frequent cause of non-specific MR or developmental delay.

The strain phase is redundant and we propose that it can be eliminated from a routine MRD protocol. This will help streamline the examination, simplify patient instructions, and reduce both imaging and reporting time.

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Rett Syndrome (RTT, OMIM 312750) is characterized by onset in the first 18 months of life of slowing and arrest of neurodevelopment paralleled with a loss of communication and motor skills acquired to that point. Purposeful hand movements are replaced by a semi-continuous hand-washing stereotype. Social interaction with the family disintegrates, resembling autistic withdrawal and, with the passage of time, a picture of profound mental retardation emerges. 1 However, depending on mutation location and extent of X-inactivation skewing, individuals with RTT may also exhibit milder phenotypes with preserved speech and ambulation, mild learning disability, or a clinical picture more similar to autism than to classical RTT. [2][3][4] Because of X-linkage, mutations causing classical RTT in girls are generally embryonic-lethal in boys, although some rare mild mutations allow survival and a variety of neurodevelopmental phenotypes in males. [5][6][7] Following mapping of the RTT candidate locus to Xq27-28, the use of a candidate gene approach allowed identification of ABSTRACT: Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder of girls, caused by mutations in the X-linked MECP2 gene. Worldwide recognition of the RTT clinical phenotype in the early 1980's allowed many cases to be diagnosed, and established RTT as one of the most common mental retardation syndromes in females. The years since then led to a refinement of the phenotype and the recent elaboration of Revised Diagnostic Criteria (RDC). Here, we study the impact of the presence versus the absence of the use of diagnostic criteria from the RDC to make a diagnosis of RTT on MECP2 mutation detection in Canadian patients diagnosed and suspected of having RTT. Methods: Using dHPLC followed by sequencing in all exons of the MECP2 gene, we compared mutation detection in a historic cohort of 35 patients diagnosed with RTT without the use of specific diagnostic criteria to a separate more recent group of 101 patients included on the basis of strict fulfillment of the RDC. Results: The MECP2 mutation detection rate was much higher in subjects diagnosed using a strict adherence to the RDC (20% vs. 72%). Conclusions: These results suggest that clinical diagnostic procedures significantly influence the rate of mutation detection in RTT, and more generally emphasize the importance of diagnostic tools in the assessment of neurobehavioral syndromes.RÉSUMÉ: Un examen clinique rigoureux améliore beaucoup la détection de mutations dans le syndrome de Rett. Introduction: Le syndrome de Rett (RTT) est une maladie neurodéveloppementale sévère observée chez les filles et causée par des mutations du gène MECP2 situé sur le chromosome X. L'identification à l'échelle mondiale du phénotype clinique du RTT au début des années 1980 a permis de diagnostiquer de nombreux cas et a démontré que le RTT est un des syndromes de retard mental les plus fréquents chez les filles. Depuis, la description du phénotype a été raffinée et des critères diagnostiques révisés (CDR) ont ...