MECP2 missense mutations outside the canonical MBD and TRD domains in males with intellectual disability

Abstract

Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.

Figure 1

Three generation pedigree of family 1 (A) and family 2 (B). The genotype at the MECP2 locus is indicated below tested individuals: +/y = hemizygous male; +/− = heterozygous female; −/− = absence of variant in female; −/y = absence of variant in male. Black symbols represent affected individuals, white symbols indicate healthy individuals and white symbols with black dots represent healthy female carriers. In panel A, the small black circle indicates a spontaneous abortion occurred at the 6th week of pregnancy.

Figure 2

Pictures of male patients with MECP2 missense variants. Upper panels show photographs of the two affected siblings of family 1 (#188): the older one is 6 years old (A), the younger one is 4 years old (B). Note the absence of peculiar facial features. Lower panels show photographs of the three patients of family 2 (#177) at the age of 42 years (C), 41 years (D) and 32 years (E), demonstrating similar phenotype with high forehead, downturned nasal tip with wide pinnae, short philtrum, thin lips, truncal obesity and large hands. In panel C, patient also presents cleft lobe of the left ear.

Figure 3

Cartoon representation of homology model of the 66E-200K MeCP2 domain obtained by Protein Model Portal. The wild type structured model of the protein is represented with the amino acid Arg167 (panel A) and the amino acid Gly185 (panel B) highlighted. Panels C and D show the mutated protein for p.Arg167Trp and p.Gly185Val variants, respectively.

Figure 4

MECP2 mutations reported in males and associated phenotypes. In each panel (A, B and C) a schematic representation of the MeCp2 protein is shown. Above protein structure, mutations found in males are indicated (Panel A: neonatal encephalopathy; Panel B: Rett spectrum phenotype; Panel C: ID/autism); below protein structure, the same mutations identified in females are reported. The phenotypes are represented as follows: neonatal encephalopathy in dark grey, Rett phenotype spectrum in light grey, ID in white and autism in striped boxes. Variants described in this paper are highlighted with hatching (panel C).