Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease.
BACKGROUND
Rett syndrome is a neurodevelopmental disorder affecting only girls; 99.5% of Rett syndrome cases are sporadic, although several familial cases have been reported. Mutations in the MECP2 gene were identified in approximately 70-80% of sporadic Rett syndrome cases.


METHODS
We have screened the MECP2 gene coding region for mutations in five familial cases of Rett syndrome and studied the patterns of X chromosome inactivation (XCI) in each girl.


RESULTS
We found a mutation in MECP2 in only one family. In the four families without mutation in MECP2, we found that (1) all mothers exhibit a totally skewed pattern of XCI; (2) six out of eight affected girls also have a totally skewed pattern of XCI; and (3) it is the paternally inherited X chromosome which is active in the patients with a skewed pattern of XCI. Given that the skewing of XCI is inherited in our families, we genotyped the whole X chromosome using 32 polymorphic markers and we show that a locus potentially responsible for the skewed XCI in these families could be located on the short arm of the X chromosome.


CONCLUSIONS
These data led us to propose a model for familial Rett syndrome transmission in which two traits are inherited, an X linked locus abnormally escaping X chromosome inactivation and the presence of a skewed XCI in carrier women.
Villard
L
L
INSERM U491, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France.
Lévy
N
N
Xiang
F
F
Kpebe
A
A
Labelle
V
V
Chevillard
C
C
Zhang
Z
Z
Schwartz
C E
CE
Tardieu
M
M
Chelly
J
J
Anvret
M
M
Fontès
M
M
D000483:Alleles; D002868:Chromosomal Proteins, Non-Histone; D020090:Chromosome Segregation / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009679:Nuclear Family; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen / Q000235:genetics; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; C497683:FMR1 protein, human; C497392:MECP2 protein, human