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M B Davis

Publications and source records attributed to M B Davis.

At least 19 recordsLinked to original sources
PubMed1998

Generalized chorea in two patients harboring the Friedreich's ataxia gene trinucleotide repeat expansion.

Recently, a trinucleotide repeat expansion in intron 1 of the frataxin gene on chromosome 9p13 has been identified as the genetic defect in Friedreich's ataxia (FA). We have identified two patients exhibiting generalized chorea in the absence of cerebellar signs who were homozygous for this intron 1 expansion. Chorea as a rare manifestation of FA has previously been controversial. This is the first report of chorea in patients confirmed to have the FA genetic abnormality and broadens further the clinical phenotype associated with the FA genotype.

Adolescent↗
PubMed1998

The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates.

The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.

Adolescent↗
PubMed1998

Endothelin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation.

Endothelin (ET)-1, alpha-melanocyte stimulating hormone (alpha-melanotropin; alpha-MSH), and basic fibroblast growth factor (bFGF) are keratinocyte-derived factors that interact synergistically to stimulate human melanocyte proliferation. ET-1 has a dose-dependent mitogenic effect on human melanocytes and a biphasic effect on melanogenesis: a stimulatory effect at subnanomolar concentrations, and an inhibitory effect at concentrations equal to or higher than 1 nM. Human melanocytes express ET B receptors. Brief treatment of melanocytes with ET-1 caused up-regulation of alpha-MSH receptor mRNA but did not alter ET B receptor mRNA level. ET-1 modulates the response of human melanocytes to UV rays (UVRs). Treatment of melanocytes with 10 nM ET-1 immediately after exposure to UVRs enabled them to overcome the G1 growth arrest. However, ET-1 did not inhibit p53 accumulation or p21(Waf-1/SDI-1/Cip-1) overexpression, nor did it reverse the hypophosphorylated state of pRb or the reduction in Bcl2 level in irradiated melanocytes. These results substantiate the role of ET-1 as a paracrine regulator that modulates the response of human melanocytes to UVRs.

Cell Division↗
PubMed1997

Myosin rod protein: a novel thick filament component of Drosophila muscle.

Myosin rod protein (MRP), a 155 kDa protein encoded by a gene internal to the Drosophila muscle myosin heavy chain (Mhc) gene, contains the MHC rod domain, but has 77 unique N-terminal residues that exactly replace the MHC motor and light chain binding domains. Originally described as an abundant testis protein, we now demonstrate the MRP also is a major component of myofilaments in Drosophila. Specifically, the Mrp promoter directs the expression of a LacZ reporter transgene in somatic, cardiac and visceral muscles. MRP-specific antibodies detect the protein in detergent-insoluble fractions of muscle extracts and co-localize the protein with MHC to the sarcomeric A-band in immunostained muscles. Immunoblot analysis shows that in a set of adult direct flight muscles (DFM), the ratio of MRP to MHC is 1:3. Chemical cross-link and co-immunoprecipitation experiments using 0.5 M KCl-extracted thick filament proteins indicate that native MRP is a homodimer. Electron microscopy of DFM49, which has a high MRP content, shows in cross section, disordered myofilament packing and a variable thin to thick filament ratio and, in longitudinal section, severely bent thin filaments that are not well associated with thick filaments. In rigor, thick filaments from DFM49 consist of segments with cross bridges that are interspersed with smooth domains lacking cross bridges. These data indicate that MRP is a novel contractile protein that co-integrates with myosin into the thick filament, thereby changing structure and function of the sarcomere.

Amino Acid Sequence↗
PubMed1997

Hereditary geniospasm: linkage to chromosome 9q13-q21 and evidence for genetic heterogeneity.

Hereditary geniospasm is an unusual movement disorder causing episodes of involuntary tremor of the chin and the lower lip. Episodes typically start in early childhood and may be precipitated by stress, concentration, and emotion. Hereditary geniospasm is inherited as an autosomal dominant trait, and its cause is not known. We report the results of a genomewide genetic linkage study in a four-generation British family with hereditary geniospasm. Positive two-point LOD scores were obtained for 15 microsatellite markers on the peri-centromeric region of chromosome 9. A maximum two-point LOD score of 5.24 at theta = .00 was obtained for the marker D9S1837. Construction of haplotypes defined an interval of 2.1 cM between the flanking markers D9S1806 and D9S175, thus assigning one locus for hereditary geniospasm to the proximal long arm of chromosome 9q13-q21. Hereditary geniospasm in a second British family is not linked to this region, indicating genetic heterogeneity. These findings may have implications for other inherited focal movement disorders that as yet remain unmapped.

Centromere↗
PubMed1997

Paroxysmal dystonic choreoathetosis. Genetic linkage studies in a British family.

Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary dystonic and choreoathetoid movements, typically several hours in duration with no sign of abnormality between attacks. Inheritance is autosomal dominant and the PDC locus has recently been assigned to the distal long arm of chromosome 2 in two families. We describe a six-generation British family with PDC and describe the results of fine genetic mapping and candidate gene linkage analysis. As part of a genome-wide search, linkage to chromosome 2q was confirmed in this family. Positive LOD scores were obtained for six markers on 2q. A LOD score of 5.08 at a recombination fraction of 0.0 was obtained for the marker D2S163. Construction of haplotypes allowed definition of a disease interval of 4 cM between the flanking markers D2S295 and D2S377. Polymorphic tandem repeats within the candidate genes CHRND (delta polypeptide of the nicotinic acetylcholine receptor) and SLC4A3 were examined yielding LOD scores of -7.68 and 6.08, respectively, at a recombination fraction of 0.0. This excludes CHRND as a candidate. Our data confirm the assignment of the locus for PDC to chromosome 2q and provide evidence for locus homogeneity in PDC. We have narrowed the disease interval to 4 cM and our findings provide support for the involvement of the gene for the chloride/bicarbonate exchanger as a candidate gene for PDC.

Athetosis↗
PubMed1997

The phenotypic manifestations of chromosome 17p11.2 duplication.

Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.

Adolescent↗
PubMed1997

Identification and sizing of the GAA trinucleotide repeat expansion of Friedreich's ataxia in 56 patients. Clinical and genetic correlates.

Fifty-six patients with a clinical diagnosis of Friedreich's ataxia were investigated for the GAA trinucleotide repeat expansion recently found within the gene X25 on chromosome 9. All 56 were found to be homozygous for the expansion, with all but two patients having alleles of differing sizes. The expansion size ranged from 2 to 5 kb, with normal alleles around 1.5 kb. Sizing of the single copy of the expansion in eight sets of parents revealed marked instability in the transmission of the expansion, with both increases and decreases in allele size seen. In Friedreich's ataxia patients there was a significant inverse correlation seen between the average of the two expansions sizes and age of onset of symptoms. The GAA repeat expansion was found in the homozygous state in atypical cases of Friedreich's ataxia, such as older age of onset, preservation of lower limb reflexes and cardiac presentations. In three families the father had onset of spinocerebellar ataxia as an adult, and in two the possibility of partial expression in heterozygote carrier fathers has been raised. More importantly, the history of an ataxic syndrome in a parent does not exclude the diagnosis of Friedreich's ataxia in the offspring, and tests for the expansion should be carried out. The third family with an affected father conforms to previously described 'pseudodominant' inheritance.

Adolescent↗
PubMed1997

Splice-junction elements and intronic sequences regulate alternative splicing of the Drosophila myosin heavy chain gene transcript.

The Drosophila muscle myosin heavy chain (Mhc) gene primary transcript contains five alternatively spliced exon groups (exon 3, 7, 9, 11 and 15), each of which contains two to five mutually exclusive members. Individual muscles typically select a specific alternative exon from each group for incorporation into the processed message. We report here on the cis-regulatory mechanisms that direct the processing of alternative exons in Mhc exon 11 in individual muscles using transgenic reporter constructs, RT-PCR and directed mutagenesis. The 6.0-kilobase exon 11 domain is sufficient to direct the correct processing of exon 11 alternatives, demonstrating that the alternative splicing cis-regulatory elements are local to Mhc exon 11. Mutational analysis of Mhc exon 11 reveals that the alternative exon nonconsensus 5'-splice donors are essential for alternative splicing regulation in general, but do not specify alternative exons for inclusion in individual muscles. Rather, we show, through exon substitutions and deletion analyses, that a 360-nucleotide intronic domain precisely directs the normal processing of one exon, Mhc exon 11e, in the indirect flight muscle. These and other data indicate that alternative exons are regulated in appropriate muscles through interactions between intronic alternative splice-specificity elements, nonconsensus exon 11 splice donors and, likely, novel exon-specific alternative splicing factors.

Alternative Splicing↗
PubMed1996

Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging.

Gramicidin perforated-patch-clamp recordings in brain slices were used to obtain an accurate assessment of the developmental change in the GABAA receptor reversal potential (EGABAA) in embryonic and early postnatal rat neocortical cells including neuroepithelial precursor cells, cortical plate neurons, and postnatal neocortical neurons. Our results demonstrate that there is a progressive negative shift in EGABAA with the most positive values found in the youngest cortical precursor cells. At the early stages of neocortical development, EGABAA is determined by the chloride (Cl-) gradient, and the internal chloride concentration ([Cl-]i) decreases with development. EGABAA is positive to the resting potential, indicating that GABA serves to depolarize developing neocortical cells. Consistent with this conclusion, GABAA receptor activation with muscimol was found-to increase the internal calcium concentration ([Ca2+]i) in both embryonic and early postnatal neocortical cells through the activation of voltage-gated calcium channels (VGCCs). Postnatal cells exhibit spontaneous postsynaptic synaptic currents, which are eliminated by bicuculline methiodide (BMI) but not glutamate receptor antagonists and reverse at the Cl- equilibrium potential. Likewise, brief spontaneous increases in [Ca2+]i, sensitive to BMI and TTX, are observed at the same ages, suggesting that endogenous synaptic GABAA receptor activation can depolarize cells and activate VGCCs. These results suggest that GABAA receptor-mediated depolarization may influence early neocortical developmental events, including neurogenesis and synaptogenesis, through the activation of Ca(2+)-dependent signal transduction pathways.

Animals↗
PubMed1996

A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis.

McLeod syndrome is an X-linked recessive disorder, characterized by neuromuscular and hematopoietic dysfunction. Two cases of McLeod syndrome were reported in a family with neuroacanthocytosis and, remarkably, 1 of them was female. Direct sequence analysis of the McLeod gene in 12 members of the family revealed a novel point mutation in exon 2 that creates a frameshift and results in premature termination of translation. There was marked skewing of X inactivation in the severely affected female.

Acanthocytes↗
PubMed1996

The human homologue of the weaver mouse gene in familial and sporadic Parkinson's disease.

The pathological hallmark of Parkinson's disease is cell death of dopaminergic neurons in the substantia nigra, resulting in striatal dopaminergic deficit and a clinical syndrome dominated by disorders of movement. The cause for this cell loss is unknown, but the possibility of a contributing genetic factor is increasingly recognized. Homozygous weaver mice, a mutant mouse strain, display progressive postnatal depletion of dopaminergic cells in the mesencephalon and have thus been proposed as an animal model for Parkinson's disease. Recently, mGIRK2, a putative G-protein inward rectifier K+ channel, has been identified as the causative gene in the weaver mouse and a homozygous mutation has been described in the H5 pore region of this channel. The human homologue of mGIRK2, KCNJ7 or hiGIRK2, has previously been isolated on chromosome 21q22.1. A possible involvement of this gene in the pathogenesis of Parkinson's disease has been discussed. To evaluate the possibility of a shared genetic defect in weaver mouse and Parkinson's disease, we analysed the H5 pore region of hiGIRK2 in familial and sporadic cases of Parkinson's disease. The sequence was normal in all cases examined, suggesting a differing aetiology of nigral cell loss in Parkinson's disease and weaver mice.

Animals↗
PubMed1996

Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy.

Pedigree analysis of British families with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skewing of X inactivation. Linkage analysis in British and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studied. Further, there was no excess skewing of X inactivation in affected females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of incomplete penetrance and male predominance in LHON remains unclear.

DNA, Mitochondrial↗
PubMed1995

Haplotype analysis of French, British and other European patients with familial amyloid polyneuropathy (met 30 and tyr 77).

Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder originally and most frequently described in Portugal. The usual constituent amyloid fibril protein is transthyretin (TTR) and the most frequent mutation in the TTR gene associated with FAP (including all Portuguese cases) is that at position 30 (met 30). Three different TTR haplotypes have been described in association with the met 30 mutation in European patients. We studied the haplotypes of 27 families (24 French, 2 British and 1 Greek) with FAP met 30 by analysing three polymorphisms in introns of the TTR gene. We also studied 6 families (2 British, 3 French and 1 Spanish) with FAP tyr 77. There were two main haplotypes in French patients with FAP met 30, one most commonly seen in the French families of Portuguese descent which was the same haplotype as previously described in Portuguese patients (haplotype I) and another haplotype (III) detected in most informative French families not of Portuguese origin. The age of onset of symptoms was consistently later in French than in Portuguese patients and in patients with haplotype III as the disease-associated haplotype rather than haplotype I. British and French patients with the tyr 77 mutation had different haplotypes. The most likely explanation of these findings is multiple founders of both mutations.

Amyloid Neuropathies↗
PubMed1995

GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis.

We have found that, during the early stages of cortical neurogenesis, both GABA and glutamate depolarize cells in the ventricular zone of rat embryonic neocortex. In the ventricular zone, glutamate acts on AMPA/kainate receptors, while GABA acts on GABAA receptors. GABA induces an inward current at resting membrane potentials, presumably owing to a high intracellular Cl- concentration maintained by furosemide-sensitive Cl- transport. GABA and glutamate also produce increases in intracellular Ca2+ in ventricular zone cells, in part through activation of voltage-gated Ca2+ channels. Furthermore, GABA and glutamate decrease the number of embryonic cortical cells synthesizing DNA. Depolarization with K+ similarly decreases DNA synthesis, suggesting that the neurotransmitters act via membrane depolarization. Applied alone, GABAA and AMPA/kainate receptor antagonists increase DNA synthesis, indicating that endogenously released amino acids influence neocortical progenitors in the cell cycle. These results demonstrate a novel role for amino acid neurotransmitters in regulating neocortical neurogenesis.

Animals↗
PubMed1995

Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy.

We investigated 99 patients from 64 European families (51 French, 11 British, one Italian and one Spanish) with suspected familial amyloid polyneuropathy (FAP) for transthyretin (TTR) gene mutations. Thirty-nine families were found to have point mutations causing the following amino acid substitutions: Met30 (28 families), Tyr77 (five), Arg 50 (one), Ala49 (one), Gln89 (one), Ala60 (one) and one each with previously undescribed mutations at Asn35 and Gys54. The clinical picture in the patients with new and known mutations were typical of FAP, without any specific features for a particular mutation. Onset of symptoms was late (over 50 years) in many French and British patients with the Met30 and Tyr77 mutations, and only 30% of all index cases had affected relatives. We propose an approach to molecular diagnosis in European patients with FAP, apart from members of families with known mutations, based on the frequency of TTR mutations observed in this and and other studies of FAP in Europe. It is logical to screen for the Met30 and Tyr77 mutations and Ala60 in the UK, using restriction enzyme analysis. If these are absent, the TTR gene should be sequenced directly to detect less common or unknown mutations.

Adult↗
PubMed1995

Loss of heterozygosity for DNA polymorphisms mapping to chromosomes 10 and 17 and prognosis in patients with gliomas.

Twenty nine patients with gliomas were investigated for loss of heterozygosity for 40 DNA polymorphisms in tumour DNA, particularly concentrating on those mapping to chromosomes 10 and 17. Eight of 18 grade IV gliomas showed loss of sequences from chromosomes 10, 17, or both. The data suggested total loss of one copy of chromosome 10, but there were interstitial deletions of the short arm of chromosome 17 in three of five tumours. Heterogeneous interstitial deletions of chromosome 17 were also found in two lower grade astrocytomas and one benign oligodendroglioma. The striking finding of this study was that patients with high grade gliomas whose tumours exhibited loss of heterozygosity for chromosomes 10, 17, or both survived significantly longer after surgery (median 17.4 months) than those whose tumours did not show loss of these chromosomes (median 6.7 months). These findings suggest that there is a subset of particularly aggressive high grade gliomas with no currently known molecular genetic abnormalities.

Adult↗