Showing papers by "Joanne E. Martin published in 2001"

A mouse Mecp2-null mutation causes neurological symptoms that mimic rett syndrome

Abstract: Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

Smooth muscle inclusion bodies in slow transit constipation

Abstract: Slow transit constipation (STC) is a disorder of intestinal motility of unknown aetiology. Myopathies, including those characterized by the finding of inclusion bodies, have been described in enteric disorders. Amphophilic inclusion bodies have been reported in the muscularis externa of the colon of STC patients. This study formally tested the hypothesis that these represent a primary muscle disorder, specific to STC. In a systematic, blinded, dual observer qualitative and quantitative analysis, colonic and ileal tissue from patients with STC (n=36) were compared with selected control populations: total colonic aganglionosis (n=10), Chagas' disease (n=6), isolated rectal evacuation disorders (n=6), and a control population of a range of ages (n=80). All sections were stained with haematoxylin and eosin and periodic acid Schiff. Further immunostains were used in an attempt to determine inclusion body composition. Round or ovoid (4-22 microm diameter) amphophilic inclusions increased in number in normal subjects with age. Inclusions were more frequent in idiopathic STC than in age-matched controls or rectal evacuation disorders [ileum (33% vs. 9%), ascending (50% vs. 19%, p<0.05), and sigmoid colon (43% vs. 20%)] and were very frequent in the sigmoid (71%) of patients with STC arising after pelvic surgery. The number of inclusions per unit area was significantly higher in patients with STC (p<0.001). Inclusions were found in all Chagas' patients, but not with aganglionosis. It was not possible to determine inclusion body composition, despite the use of a wide range of conventional and immunostains. This study demonstrates that inclusion body myopathy is identifiable in patients with STC and that it may arise secondary to denervation.

Identification Of Two New Pmp22 Mouse Mutants Using Large‐Scale Mutagenesis And A Novel Rapid Mapping Strategy

Abstract: Mouse mutants have a key role in discerning mammalian gene function and modelling human disease; however, at present mutants exist for only 1-2% of all mouse genes. In order to address this phenotype gap, we have embarked on a genome-wide, phenotype-driven, large-scale N-ethyl-N--nitrosourea (ENU) mutagenesis screen for dominant mutations of clinical and pharmacological interest in the mouse. Here we describe the identification of two similar neurological phenotypes and determination of the underlying mutations using a novel rapid mapping strategy incorporating speed back-crosses and high throughput genotyping. Two mutant mice were identified with marked resting tremor and further characterized using the SHIRPA behavioural and functional assessment protocol. Back-cross animals were generated using in vitro fertilization and genome scans performed utilizing DNA pools derived from multiple mutant mice. Both mutants were mapped to a region on chromosome 11 containing the peripheral myelin protein 22 gene (Pmp22). Sequence analysis revealed novel point mutations in Pmp22 in both lines. The first mutation, H12R, alters the same amino acid as in the severe human peripheral neuropathy Dejerine Sottas syndrome and Y153TER in the other mutant truncates the Pmp22 protein by seven amino acids. Histological analysis of both lines revealed hypo-myelination of peripheral nerves. This is the first report of the generation of a clinically relevant neurological mutant and its rapid genetic characterization from a large-scale mutagenesis screen for dominant phenotypes in the mouse, and validates the use of large-scale screens to generate desired clinical phenotypes in mice.