MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation.
Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype-genotype correlation could thus be suspected and is discussed in these three families.
Gomot
Marie
M
Service de Génétique, CHU Bretomeau, INSERM U316, 2 boulevard Tonnellé, 37044 Tours cedex, France. m.gomot@chu-tours.fr
Gendrot
Chantal
C
Verloes
Alain
A
Raynaud
Martine
M
David
Albert
A
Yntema
Helger G
HG
Dessay
Sabine
S
Kalscheuer
Vera
V
Frints
Suzanne
S
Couvert
Philippe
P
Briault
Sylvain
S
Blesson
Sophie
S
Toutain
Annick
A
Chelly
Jamel
J
Desportes
Vincent
V
Moraine
Claude
C
D000328:Adult; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D040461:Gene Components; D005838:Genotype; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics; D013064:Speech Disorders / Q000235:genetics
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins