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

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) 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 affect conserved domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codon 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 domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Figure 1

Sporadic and familial mutations in MECP2. A, Sequence tracings of six mutations, including the normal variant 1189G→A. B, R168X mutation, identified by a mutation-induced cleavage at a HphI site. The mother and two affected daughters are heterozygotes. C, 806delG frameshift mutation, identified by loss of an NlaIV site. Two females with RTT, the obligate carrier, and the affected male are positive for the diagnostic 365-bp fragment. There is no evidence for somatic mosaicism in I-3, who transmitted the mutation to her two daughters.

Figure 2

MECP2 mutations in Rett syndrome. The structure of the human MECP2 gene is derived from the genomic sequence (GenBank AF030876). The functional domains were defined by Nan et al. (1993, 1997).