Rett syndrome and beyond: Recurrent spontaneous and familial MECP2 mutations at CpG hotspots

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. Th e responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was rece ntly discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R3 06C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and a ffect conserved domains of MeCP2. All of the nucleotide substitutions invol ve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codo n 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression doma in was identified in a woman with motor-coordination problems, mild learnin g disability, and skewed X inactivation; in her sister and daughter, who we re affected with classic RTT; and in her hemizygous son, who died from cong enital encephalopathy. Thus, some males with RTT-causing MECP2 mutations ma y survive to birth, and female heterozygotes with favorably skewed X-inacti vation patterns may have little or no involvement. Therefore, MECP2 mutatio ns are not limited to RTT and may be implicated in a much broader phenotypi c spectrum.