MECP2 – Rett Syndrome

MECP2 encodes methyl-CpG-binding protein 2, a key transcriptional regulator expressed ubiquitously but with critical postnatal roles in neurons. Pathogenic variants in MECP2 cause Rett syndrome (MONDO:0010726), an X-linked dominant neurodevelopmental disorder characterized by normal early development followed by regression of motor and verbal skills, stereotypic hand movements, microcephaly, and seizures. Male hemizygotes typically exhibit severe neonatal encephalopathy, although somatic mosaicism can result in classic features (PMID:11071498).

1 Assess Clinical Validity

Overall association: Definitive. MECP2 mutations are identified in 70–95% of classic Rett syndrome patients across multiple cohorts (24/31 probands (PMID:10814718); >1,900 cases in the IRSA database), with recurrent hotspots (T158M, R168X, R255X, R270X, R306C) and strong concordance between genotype and phenotype. Segregation in familial cases and functional concordance support a definitive classification.

2 Genetic Evidence

Inheritance: X-linked dominant. Segregation: three additional affected relatives in a multigenerational family carrying the T158M mutation (PMID:11071498). Case series encompass >900 unrelated patients harboring over 100 distinct pathogenic variants, including truncating, missense, and frameshift mutations in the methyl-CpG-binding domain and transcriptional repression domain. Frequent recurrent variants occur at CpG dinucleotide hotspots. Carrier frequency in males is exceedingly rare; skewed X-inactivation explains variable expressivity in females.

Selected pathogenic variant: c.91C>T (p.Gln31Ter) (PMID:10737989).

3 Functional / Experimental Evidence

Mechanism: loss of MeCP2 function via haploinsufficiency. Mecp2-null and CNS-specific knockout mice recapitulate key Rett features, including motor deficits, reduced neuronal size, and premature lethality (PMID:11242118). In vitro assays of MBD missense mutations (R106W, R133C, F155S, T158M) demonstrate impaired binding to methylated DNA and reduced transcriptional repression (PMID:10852707). Transcriptome profiling reveals subtle, but consistent, deregulation of neuronal gene expression.

4 Conflicting Evidence

Variants outside functional domains and synonymous changes often represent benign polymorphisms; comprehensive parental analysis and X-inactivation studies are essential to distinguish pathogenicity.

5 Conclusion

Extensive genetic and functional data establish MECP2 as the definitive cause of Rett syndrome. Routine MECP2 screening in classical RTT is clinically useful for diagnosis, prognostic stratification, and genetic counseling. Functional insights underpin future therapeutic avenues targeting MeCP2-mediated chromatin regulation.

Key Take-home: MECP2 mutation testing is clinically imperative for girls with classic Rett syndrome, guiding diagnosis and management.

References

• Human molecular genetics • 2000 • Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. PMID:10814718
• Neurology • 2000 • Two affected boys in a Rett syndrome family: clinical and molecular findings. PMID:11071498
• Biochemistry • 2000 • Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. PMID:10852707
• Nature genetics • 2001 • Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. PMID:11242118

Evidence Based Scoring (AI generated)