Effect of genetic background on acoustic startle response in fragile X knockout mice.

To study the effect of genetic background on the Fmr1 knockout mutation in mice, we compared the acoustic startle response (ASR) of male fragile X knockout mice bred in three different genetic backgrounds, including C57BL/6J (C57BL/6J x 129P2/OlaHsd) F1 and F2 intercross. ASR is used as a behavioural tool to assess the neuronal basis of behavioural plasticity. For each background studied, fragile X knockouts clearly differed in ASR from their control littermates. C57BL/6J knockouts showed an increase in ASR in response to the lowest stimulus of 90 dB and a decrease in ASR in response to the highest stimulus of 110 dB when compared with control mice, whereas knockouts of the F1 generation showed significantly lower ASRs for all the three stimulus intensities used when compared with control littermates. These data demonstrate that the expression of the fragile X phenotype in ASR of fragile X knockout mice may be influenced by the presence of 129 genes in the genetic background and that modifier genes may influence the fragile X phenotype. Surprisingly, and in contrast with knockouts of the F1 generation that showed a decreased ASR, knockouts of the F2 generation showed a significantly increased ASR compared with their control littermates. This is especially remarkable as both F1 and F2 mice consist of 50% of the genetic material from each of the parental strains C57BL/6J and 129P2/OlaHsd strain. Thus, the different distribution of the genetic background seems to be responsible for the difference in ASR between F1 and F2. This opposite ASR in the F1 and F2 generations is unique in behavioural studies and has, to our knowledge, not been previously reported.

Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS).

Carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are spared the major neurodevelopmental symptomatology of fragile X syndrome patients carrying a full mutation (>200 repeats). In a proportion of premutation carriers, the repeat expansion is associated with a specific neurological profile involving intention tremor, ataxia, intellectual decline compatible with dementia syndrome, Parkinsonism and autonomic dysfunction at older age, commonly referred to as fragile-X-associated tremor/ataxia syndrome (FXTAS). Typical CNS changes include hyperintense signals on T2 weighted magnetic resonance images and the presence of ubiquitin-positive intranuclear neuronal inclusions. A knock-in mouse model with a (CGG)98 repeat in the premutation range has been generated and shown to exhibit elevated Fmr1 mRNA levels and ubiquitin-positive intranuclear neuronal inclusions, suggesting it may be a valid model for the human disease. Given the specific clinical profile of FXTAS patients, the expanded CGG repeat model was assessed for cognitive, behavioural and neuromotor performance at different ages (20, 52 and 72 weeks). The Morris water maze task exposed age-dependent decline of visual-spatial memory. Open field recordings revealed decreased exploration of the centre of the arena in the oldest group of expanded CGG repeat mice, potentially reflecting increased anxiety. Neuromotor tasks primarily showed decline of performance on the accelerating rotarod with age in the premutation carriers but not in control littermates. The age-dependent cognitive decline and neuromotor disturbances may be related to the progressive cognitive and behavioural difficulties observed in FXTAS patients.

Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening?

Mutations in the methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome, a severe neurodevelopmental disorder occurring predominantly in females. Male patients with Rett syndrome are extremely rare, as the Rett-causing mutations in the MECP2 gene are usually lethal in hemizygous males. However, different mutations in the same gene were reported to cause mental retardation, both in sporadic non-syndromic males as well as in syndromic families with disease manifestation in carrier females. The majority of the reported MECP2 mutations in mentally retarded patients cause amino acid substitutions and, especially in isolated cases, discrimination between a disease-causing mutation and a rare polymorphism is not obvious and the significance of each individual variation should be verified. We mapped a new non-syndromic X-linked family (MRX79) to the chromosomal region Xq27.3-Xq28 and identified an A140V mutation in the MEPC2 gene in all patients with the disease haplotype. In addition to data published by others, this suggests that A140V is a recurrent mutation (and not a polymorphism) found in patients with X-linked mental retardation.

Family MRX9 revisited: further evidence for locus heterogeneity in MRX.

Nonspecific X-linked mental retardation (MRX) patients are characterized by mental retardation, without additional distinguishing features. Consequently, MRX families can only be distinguished by mapping studies; yet, due to imprecise mapping studies performed in the past, the number of genes causing MRX is debatable, and a more precise localization for families is necessary to estimate this number. MRX 9 has been mapped to the pericentromeric region Xp21-q13. We refined the mapping of the MRX9 family to Xp11.22-Xp11.4. A sequencing analysis of three likely candidate genes in Xp11, SREB3, synapsin I, and TM4SF2, revealed no mutations.