Biomedical subjects

Howard Slater

Publications and source records attributed to Howard Slater.

3 recordsLinked to original sources

PubMed2005

Effect of Turner's syndrome and X-linked imprinting on cognitive status: analysis based on pedigree data.

The effects of a monosomy of either the maternally or paternally derived X chromosome in Turner's syndrome (TS) on general neurocognitive status and some executive abilities were assessed using the maximum likelihood estimators for pedigree data. This method increases the power of analysis by accounting for the effect of background heritable variation on a trait. The sample comprised 42 females with regular non-mosaic X monosomy and their non-affected relatives. Wechsler neurocognitive scores and several executive function tests' scores, including the Behaviour Dyscontrol Scale (BDS-2), the Wisconsin Card Sorting Test (WCST), and the Rey Complex Figure Test (RCFT), were considered in the analysis. Results showed a significant effect of TS on all Wechsler index and subtest scores, with greatest deficits observed in Arithmetic, Block Design, Object Assembly and Picture Arrangement, and on the total BDS, RCFT and WCST scores, regardless of parental origin of the single X-chromosome. Our data also showed a significantly higher effect of a paternally derived X chromosome in diminishing the performance on several Wechsler scores relevant to verbal skills, which might suggest X-linked imprinting loci relevant to these skills. Possible reasons for the inconsistency of the results concerning X-linked imprinting of cognitive loci using TS patients are discussed, and the relevance of pedigree analysis to future studies of this problem is emphasized.

Adolescent↗

PubMed2004

Human centromere repositioning "in progress".

Centromere repositioning provides a potentially powerful evolutionary force for reproductive isolation and speciation, but the underlying mechanisms remain ill-defined. An attractive model is through the simultaneous inactivation of a normal centromere and the formation of a new centromere at a hitherto noncentromeric chromosomal location with minimal detrimental effect. We report a two-generation family in which the centromeric activity of one chromosome 4 has been relocated to a euchromatic site at 4q21.3 through the epigenetic formation of a neocentromere in otherwise cytogenetically normal and mitotically stable karyotypes. Strong epigenetic inactivation of the original centromere is suggested by retention of 1.3 megabases of centromeric alpha-satellite DNA, absence of detectable molecular alteration in chromosome 4-centromereproximal p- and q-arm sequences, and failure of the inactive centromere to be reactivated through extensive culturing or treatment with histone deacetylase inhibitor trichostatin A. The neocentromere binds functionally essential centromere proteins (CENP-A, CENP-C, CENP-E, CENP-I, BUB1, and HP1), although a moderate reduction in CENP-A binding and sister-chromatid cohesion compared with the typical centromeres suggests possible underlying structural/functional differences. The stable mitotic and meiotic transmissibility of this pseudodicentric-neocentric chromosome in healthy individuals and the ability of the neocentric activity to form in a euchromatic site in preference to a preexisting alphoid domain provide direct evidence for an inherent mechanism of human centromere repositioning and karyotype evolution "in progress." We discuss the wider implication of such a mechanism for meiotic drive and the evolution of primate and other species.

Autoantigens↗

PubMed2004

Improved testing for CMT1A and HNPP using multiplex ligation-dependent probe amplification (MLPA) with rapid DNA preparations: comparison with the interphase FISH method.

Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are the two most common peripheral neuropathies, with incidences of about 1 in 2,500. Several techniques can be used to detect the typical 1.5-Mb duplication or deletion associated with these respective conditions, but none combines simplicity with high sensitivity. MLPA is a new technique for measuring sequence dosage. We have assessed its performance for the detection of the specific 1.5-Mb duplication/deletion by prospectively testing 50 patients referred with differential diagnoses of CMT or HNPP. Probes were designed to evaluate the TEKT3, PMP22, and COX10 genes within the CMT1A/HNPP region. We have compared the results with our existing fluorescence in situ hybridization (FISH) assay, which was performed in parallel. There was concordance of results for 49 patients. Of note, one patient showed an intermediate multiplex ligation-dependent probe amplification (MLPA) result with an abnormal FISH result, which is consistent with mosaicism. The assay works equally well with either purified DNA or rapid DNA preparations made by direct cell lysis. The use of the latter significantly reduces the cost of the assay. MLPA is a sensitive, specific, robust, and cost-effective technique suitable for fast, high-throughput testing and offers distinct advantages over other testing methods.

Charcot-Marie-Tooth Disease↗