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Zhang J, Bao X, Cao G, Jiang S, Zhu X, Lu H, Jia L, Pan H, Fehr S,Davis M, Leonard H, Ravine D, Wu X. What does the nature of the MECP2 mutation tell us about parental origin and recurrence risk in Rett syndrome?
Rett syndrome is associated with mutations in the MECP2 gene which is located on the X chromosome. The disorder principally affects females and most cases arise due to spontaneous mutations and in only a few cases is the mutation inherited from the mother (0.5%). We therefore hypothesised that mutations occur predominantly on the male derived X chromosome.
What we did
DNA was obtained from patients and both parents. Each patient has two MECP2 genes, one on the paternal allele and one on the maternal allele. Single nucleotide polymorphisms (SNPs) are variations in the DNA code that can be used to identify individuals. If the patient had only one copy of a SNP within the MECP2 gene then we could look at the parents DNA to see which one of them had the same SNP in their MECP2 gene. This allowed us to determine the parent of origin of the patient's alleles and hence the parental origin of the mutation.
What we found
Parental origin of mutation was determined for 12 of 22 cases of which 11 had paternal origin. These cases were pooled with results from a previous experiment. In the pooled sample, 122 cases had a paternally derived and 19 a maternally derived mutation. We also noted that the spectrum of mutations differed between maternally and paternally derived chromosomes. Single nucleotide substitutions were more frequently observed in paternally derived mutations (90/122) and early truncating frameshift mutations and single nucleotide gains and losses were more evident in maternally derived mutations.
What does it mean
Our findings suggest a parental-gender influence on mutation types which has also been observed in X-linked Duchene Muscular Dystrophy. Male mutation bias is a known phenomenon that is likely due to the fact that spermatogenesis is ongoing in the male with sperm undergoing more cell divisions and thus more susceptible to mutations than oocytes which are fully developed at the time of female birth.
For further reports and findings, see our publications list.