Roberts syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts syndrome in 15 kindreds. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
We recorded evoked potentials (EPs) induced by conventional transcutaneous electrical stimulation (TS), laser stimulation (LS) and epidermal electrical stimulation (ES) using a specially made needle electrode. We evaluated the activated fibers by epidermal stimulation by assessing the conduction velocity (CV) of the peripheral nerves. The EPs were recorded from Cz electrode (vertex) of the International 10-20 system in 12 healthy subjects. For the ES, the tip of a stainless steel needle electrode was inserted in the epidermis of the skin (0.2 mm in depth). Distal and proximal sites of the upper limb were stimulated by the LS and ES with an intensity which induced a definite pain sensation. Similar sites were stimulated by TS with an intensity of two times the sensory threshold. A major EP positive response (P1) was obtained by stimulation by all three types of stimuli. The P1 latency for the TS (245+/-22 ms) was significantly shorter than that for the ES (302+/-17 ms, P<0.0001) and LS (341+/-21 ms, P<0.0001) and the peak latency P1 by the LS was also significantly longer, approximately 40 ms, than that by the ES (P<0.0001). The CVs were 15.1, 15.3 and 44.1 m/s obtained by ES, LS and TS, respectively. The CV indicated that the fibers activated by the ES were mainly A fibers, which corresponded to the fibers stimulated by the LS. We considered that the ES with our newly developed needle electrode was a very convenient method for the selective stimulation of the A fibers, since it was very simple, not requiring any special apparatus, did not cause bleeding or burns and caused minimum uncomfortable feeling.
Although numerous anatomical and electrophysiological findings in animal studies have supported a hierarchical scheme of somatosensory processing, precise activation timings of each cortical area are not known. Therefore we examined the temporal relationship of activities among multiple cortical areas using magnetoencephalography in humans. We found activations in Brodmann's areas 3b, 4, 1, 5 and the secondary somatosensory cortex region in the right hemisphere following transcutaneous electrical stimulation of the dorsum of the left hand. The mean onset latencies of each cortical activity were 14.4, 14.5, 18.0, 22.4 and 21.7 ms, respectively. The differences of onset latencies among these activations indicated the serial mode of processing both through the postcentral gyrus and through the primary and secondary somatosensory cortices.
The cDNA for a murine galactocerebrosidase was isolated from a murine testis cDNA library on the basis of its homology with the cDNA for human galactocerebrosidase and a PCR method was used to clone the 5′ end. It has a 2,278‐nucleotide sequence including a 2,004‐nucleotide open reading frame, which encodes 668 amino acid residues. The identity between the human and murine amino acid sequences was very high, being calculated to be 84%. Sequencing of cDNA from liver of the twitcher mouse revealed a nonsense mutation at codon 339 (TGG → TGA). The most abundant mRNA of the murine galactocerebrosidase gave a 3.6‐kb band, which was not detected in twitcher mice. This suggests that the cDNA (2,278 bp) we characterized represents a minor species generated by an alternate poly(A) signal and that most of the mRNA has a much longer 3′‐untranslated region. Genome analysis revealed that this mutation was homozygous in the twitcher and heterozygous in the carrier but was not present in normal mice. The normal mouse cDNA but not the mutant cDNA of the galactocerebrosidase transfected into COS1 cells gave rise to an increase in enzymatic activity. We concluded that this mutation results in the deficiency of galactocerebrosidase in the twitcher mouse.
Wilson disease (WD), an autosomal recessive disorder of copper transport, is characterized by impaired biliary excretion and by impaired incorporation of copper into ceruloplasmin. Toxic accumulation of copper causes tissue damage, primarily in the liver, brain, and kidneys. The gene for WD (ATP7B) has been cloned, and the protein product is predicted to be a copper-transporting P-type ATPase with high amino acid identity with that for Menkes disease, an X-linked disorder of copper transport. Mutation screening in WD patients has led to the identification of at least 40 mutations. In addition, haplotype analysis using three dinucleotide-repeat markers, D13S314, D13S301, and D13S316, has been a useful indicator of specific mutations. We have determined haplotypes for the patients and their parents and sibs, in 21 unrelated WD families from Japan. Twenty-eight different haplotypes were observed on 42 WD chromosomes. In all the patients, the ATP7B coding sequence, including the intron-exon boundaries, was screened for mutations, by SSCP, followed by direct-sequence analysis of the shifted fragments. We identified 13 mutations, of which 11 mutations are novel, including 7 mutations-1 insertion, 4 deletions, and 2 missense mutations-in the coding region. The mutations reported in previous studies are 2299insC and Arg778Leu. Two patients were shown to have the 2299insC mutation, which has occurred in many different haplotypes in several populations, indicating a mutation hot spot. Primer-extension analysis of ATP7B mRNA has revealed multiple transcription start sites. Four of the novel mutations (three 1-bp changes and one 5-bp deletion) occur in the 5' UTR and may result in altered expression of the WD gene.
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