MECP2 missense mutations outside the canonical MBD and TRD domains in males with intellectual disability.
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.
Medical Genetics, University of Siena, Siena, Italy.
Laura
L
Bianciardi
Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina (EN), Italy.|Department of Biomedical and Biotechnological Sciences, Medical Genetics, University of Catania, Catania, Italy.
Marco
M
Fichera
Paediatrics and Medical Genetics Unit, IRCCS Associazione Oasi Maria Santissima, Troina (EN), Italy.
Pinella
P
Failla
Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Chiara
C
Di Marco
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
Detelina
D
Grozeva
Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Maria Antonietta
MA
Mencarelli
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
Ottavia
O
Spiga
Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Francesca
F
Mari
Medical Genetics, University of Siena, Siena, Italy.
Ilaria
I
Meloni
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
Lucy
L
Raymond
Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Alessandra
A
Renieri
Paediatrics and Medical Genetics Unit, IRCCS Associazione Oasi Maria Santissima, Troina (EN), Italy.
Corrado
C
Romano
Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Francesca
F
Ariani
D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D000072417:Protein Domains / Q000235:genetics
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2