Abstract
BackgroundRett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX.ResultsWe report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis.ConclusionWe have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.
Highlights
Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene
Generation of the MeCP2 A140V mutant mouse The A140V mouse model of RTT/X-linked mental retardation (XLMR) was generated by introducing a point mutation that results in the A140V missense mutation of MeCP2 protein
(5’-end) were sequenced to verify that they were hemizygous for the A140V mutation and two of these clones were used for blastocyst injection
Summary
Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Some MECP2 mutations can lead to diseases characterized as mental retardation syndromes, in boys One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Pathological studies of human RTT cases have shown a reduction in brain size, and an increase in cell packing density [5,6] These studies have noted a significant reduction in the dendritic branching of neurons in specific layers of the frontal, motor, temporal and limbic cortex [6,7,8,9]
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