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Biomedical subjects

R G Snell

Publications and source records attributed to R G Snell.

At least 19 recordsLinked to original sources
PubMed2005

TATA-binding protein in neurodegenerative disease.

TATA binding protein (TBP) is a general transcription factor that plays an important role in initiation of transcription. In recent years evidence has emerged implicating TPB in the molecular mechanism of a number of neurodegenerative diseases. Wild type TBP in humans contains a long polyglutamine stretch ranging in size from 29 to 42. It has been found associated with aggregated proteins in several of the polyglutamine disorders. Expansion in the CAA/CAG composite repeat beyond 42 has been shown to cause a cerebellar ataxia, SCA17. The involvement of such an important housekeeping protein in the disease mechanism suggests a major impact on the functioning of cells. The question remains, does TBP contribute to these diseases through a loss of normal function, likely to be catastrophic to a cell, or the gain of an aberrant function? This review deals with the function of TBP in transcription and cell function. The distribution of the polyglutamine coding allele lengths in TBP of the normal population and in SCA17 is reviewed and an outline is given on the reported cases of SCA17. The role of TBP in other polyglutamine disorders will be addressed as well as its possible role in other neurodegenerative diseases.

Animals↗
PubMed2005

Emerging technologies for identifying superior dairy cows in New Zealand.

The performance of animals is determined by the interaction of their genes with environmental circumstances. Accordingly, animals exhibiting superior performance are not necessarily the animals with the best genes nor are they the best choice of parents. Statistical analyses of production records for repeated traits, e.g. lactation yields and reproductive performance, show that part of the variation in performance among animals in the same herd and year is due to genetic differences, and the remainder is due to so-called residual or environmental factors that are not passed on to offspring. These within-herd environmental factors can be partitioned into a component that affects performance throughout an animal's lifetime, and a part that is unique to each observation. The process of animal evaluation from pedigree and performance records partitions the superiority of each cow into these three components. Reliable assessment of the genetic merit of bulls has required progeny testing, and for cows has required observation of their own individual performance. Selection on the genetic or breeding value component has systematically improved animal performance over recent decades, but has been limited by the age at which assessments of genetic merit are available. Emerging molecular technologies can read DNA sequences or measure RNA expression and have allowed the identification of a number of chromosome regions, and a few specific genes in those regions, that influence economic performance. This information allows better characterisation of the relationships between animals and more accurate predictions of genetic merit in bulls without progeny information and in cows that have yet to produce their own performance record. At some stage, enough genes responsible for variation in performance will be identified to allow faster genetic progress through selection of animals at young ages and therefore more rapid turnover of the generations. Mechanisms that modify gene expression have been identified and these may ultimately allow animals to be selected at an early age for lifetime productivity, accounting for processes that modify gene expression and lead to differences in performance that are not reflected by DNA sequence information. This review describes the status of these emerging technologies and their likely role in the improvement of dairy cattle.

Animals↗
PubMed2003

Distribution of gephyrin in the human brain: an immunohistochemical analysis.

Gephyrin is an ubiquitously expressed protein that, in the central nervous system, generates a protein scaffold to anchor inhibitory neurotransmitter receptors in the postsynaptic membrane. It was first identified as a protein component of the glycine receptor complex. Recent studies have demonstrated that gephyrin is colocalized with several subtypes of GABA(A) receptors and is part of postsynaptic GABA(A) receptor clusters. Here, we describe a study of the regional and cellular distribution of gephyrin in the human brain, determined by immunohistochemical localisation at the light and confocal laser scanning microscopic levels. At the regional level, gephyrin immunoreactivity was observed in most of the major brain regions examined. The most intense staining was in the cerebral cortex, hippocampus and caudate-putamen, in various brainstem nuclei with more moderate levels in the thalamus and cerebellum. At the cellular level gephyrin immunoreactivity was present on the plasma membranes of the soma and dendrites of pyramidal neurons throughout the various cortical regions examined. In the hippocampus, intense staining was observed on the granule cells of the dentate gyrus, and neurons of the CA1 and CA3 regions showed intense punctate gephyrin staining on their apical dendrites and cell bodies. Gephyrin immunoreactivity was also observed on neurons in the thalamus, globus pallidus and substantia nigra. In the putamen intense labelling of the striosomes was observed; most of the medium-sized neurons in the caudate-putamen were weakly labelled and many large neurons of the striatum were conspicuously stained. Many of the brainstem nuclei, notably the dorsal motor nucleus of the vagus, hypoglossal nucleus, trigeminal nucleus and inferior olive were all labelled with gephyrin. The spinal cord also showed high levels of gephyrin immunoreactivity. Our results demonstrate that the anchoring protein gephyrin is ubiquitously present in the human brain. We therefore suggest that gephyrin may have a central organizer role in assembling and stabilizing inhibitory postsynaptic membranes in human brain and is similar in function to those observed in the rodent brain. These findings contribute towards elucidating the role of gephyrin in the human brain.

Aged↗
PubMed2003

Association of gephyrin and glycine receptors in the human brainstem and spinal cord: an immunohistochemical analysis.

Gephyrin is a postsynaptic clustering molecule that forms a protein scaffold to anchor inhibitory neurotransmitter receptors at the postsynaptic membrane of neurons. Gephyrin was first identified as a protein component of the glycine receptor complex and is also colocalized with several GABAA receptor subunits in rodent brain. We have studied the distribution of gephyrin and glycine receptor subunits in the human brainstem and spinal cord using immunohistochemistry at light and confocal laser scanning microscopy levels. This study demonstrates the novel localization of gephyrin with glycine receptors in the human brainstem and spinal cord. Colocalization of immunoreactivities for gephyrin and glycine receptor subunits was detected in the dorsal and ventral horns of the spinal cord, the hypoglossal nucleus and the medial vestibular nucleus of the medulla. The results clearly establish that gephyrin is ubiquitously distributed and is colocalized, with a large proportion of glycine receptor subunits in the human brainstem and spinal cord. We therefore suggest that gephyrin functions as a clustering molecule for major subtypes of glycine receptors in the human CNS.

Aged↗
PubMed2002

Characterization of the DGAT1 gene in the New Zealand dairy population.

Recently, DGAT1 was identified as the gene that underlies the QTL for bovine milk production on chromosome 14. This study investigated the effect of the reported polymorphism in three dairy breeds in New Zealand. Statistically significant results were identified for milk fat, milk protein, and volume for Jersey and Holstein-Friesian breeds, and only milk volume for Ayrshires. The average allele substitution effects were 2 to 3 kg of protein and 120 to 130 l milk for both the Jersey and Holstein-Friesian breeds. For milk fat, the average allele substitution effect was 6 kg for Holstein-Friesians and 3 kg for Jerseys. In all breeds, where the polymorphism increased milk fat yield, it decreased milk protein yield and milk volume.

Acyltransferases↗
PubMed2001

Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.

The alpha(1)-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding alpha1-subunits and two structural beta-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with hyperekplexia and hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.

Amino Acid Sequence↗
PubMed2000

Further evidence of autosomal dominant congenital zonular pulverulent cataracts linked to 13q11 (CZP3) and a novel mutation in connexin 46 (GJA3).

We describe a four-generation family with fully penetrant, autosomal dominant, congenital cataracts (ADCC), presenting with morphologically homogeneous "zonular pulverulent" cataracts (CZP) and typical early-onset phenotype. Linkage analysis was performed with a panel of polymorphic markers mapped to all genomic regions of ADCC susceptibility. Contiguous significant two-point lod scores were generated at autosomal region 13q11-q13 and further linkage and haplotype studies confined the disease locus to 13q11, supporting a previous linkage of CZP (specifically CZP3) to 13q11. Mutations in a gap-junction protein, connexin 46 (alphaa3 subunit or GJA3), have recently been reported as being linked to the 13q11 region. Mutational analysis of connexin 46 in our family revealed a C-->T at position 560 (P187L) of the cDNA sequence creating a novel MnlI restriction site that segregated with affected members of the pedigree. This family represents a second report of CZP3 linkage to 13q and is associated with a novel mutation in the connexin 46 (GJA3) gene.

Base Sequence↗
PubMed2000

Amyloid-like inclusions in Huntington's disease.

Huntington's disease is a progressive, autosomal dominantly inherited, neurodegenerative disease that is characterized by involuntary movements (chorea), cognitive decline and psychiatric manifestations. This is one of a number of late-onset neurodegenerative disorders caused by expanded glutamine repeats, with a likely similar biochemical basis. Immunohistochemical studies on Huntington's disease tissue, using antibodies raised to the N-terminal region of huntingtin (adjacent to the repeat) and ubiquitin, have recently identified neuronal inclusions within densely stained neuronal nuclei, peri-nuclear and within dystrophic neuritic processes. However, the functional significance of inclusions is unknown. It has been suggested that the disease-causing mechanism in Huntington's disease (and the other polyglutamine disorders) is the ability of polyglutamine to undergo a conformational change that can lead to the formation of very stable anti-parallel beta-sheets; more specifically, amyloid structures. We examined, using Congo Red staining and both polarizing and confocal microscopy, post mortem human brain tissue from five Huntington's disease cases, two Alzheimer's disease cases and two normal controls. Brains from five transgenic mice (R6/2)(12) expressing exon 1 of the human huntingtin gene with expanded polyglutamine, and five littermate controls, were also examined by the same techniques. We have shown that some inclusions in Huntington's disease brain tissue possess an amyloid-like structure, suggesting parallels with other amyloid-associated diseases such as Alzheimer's and prion diseases.

Alzheimer Disease↗
PubMed1997

Structure and sequence of the bovine butyrophilin gene.

The complete sequence of the bovine butyrophilin gene (BTN) is described and compared with the mouse gene (Btn). Both genes contain seven exons separated by six introns, and the organisation of exons is closely associated with structural domains of the protein. Individual exons of BTN and Btn are 68-87% similar in sequence. There are no canonical TATA or CCAAT boxes associated with the transcription initiation sites in the genes of either species. However, a number of potential binding sites for transcription factors were identified in the 5'-flanking DNA, some of which may function in regulating expression of the gene in mammary tissue. Conservation of a 110-bp region in the promoters of BTN and Btn may have some functional significance. Cloning and sequencing of BTN provides an additional mammary-specific gene promoter that may be used for driving the expression of transgenes in the lactating mammary gland, and for determining the basis for tissue-specific gene expression. In addition, the sequence of BTN may be used to map intragenic polymorphisms and identify quantitative trait loci in commercial livestock.

Animals↗
PubMed1997

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

Amino Acid Sequence↗
PubMed1997

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression.

The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not continuous GH exposure activates liver STAT5b by tyrosine phosphorylation, leading to dimerization, nuclear translocation, and transcriptional activation of the STAT, which is proposed to play a key role in regulating the sexual dimorphism of liver gene expression induced by pulsatile plasma GH. We have evaluated the importance of STAT5b for the physiological effects of GH pulses using a mouse gene knockout model. STAT5b gene disruption led to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitary GH secretion. Male-characteristic body growth rates and male-specific liver gene expression were decreased to wild-type female levels in STAT5b-/- males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH-deficient Little mice, STAT5b-/- mice are not GH-deficient, suggesting that they may be GH pulse-resistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b-/- mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests that STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps other target tissues. STAT5b thus has unique physiological functions for which, surprisingly, the highly homologous STAT5a is unable to substitute.

Animals↗
PubMed1997

Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by the development of hamartomatous growths in many organs. Sixty to seventy percent of cases are sporadic and appear to represent new mutations. TSC exhibits locus heterogeneity: the TSC2 gene is located at 16p13.3 whilst the TSC1 gene, predicted to encode a novel protein termed hamartin, has recently been cloned from 9q34. With the exception of a contiguous gene deletion syndrome involving TSC2 and PKD1 , TSC1 and TSC2 phenotypes have been considered identical. We have now comprehensively defined the TSC1 mutational spectrum in 171 sequentially ascertained, unrelated TSC patients by single strand conformation polymorphism and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus. Mutations were identified in 9/24 familial cases, but in only 13/147 sporadic cases. In contrast, a limited screen revealed TSC2 mutations in two of the familial cases and in 45 of the sporadic cases. Thus TSC1 mutations were significantly under-represented among sporadic cases (Fisher's exact p -value = 3.12 x 10(-4)). Both large deletions and missense mutations were common at the TSC2 locus whereas most TSC1 mutations were small truncating lesions. Mental retardation was significantly less frequent among carriers of TSC1 than TSC2 mutations (odds ratio 5.54 for sporadic cases only, 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included). No correlation between mental retardation and the type of mutation was found. We conclude that there is a reduced risk of mental retardation in TSC1 as opposed to TSC2 disease and that consequent ascertainment bias, at least in part, explains the relative paucity of TSC1 mutations in sporadic TSC.

Humans↗
PubMed1994

Late-onset Huntington's disease: a clinical and molecular study.

Using the Huntington's disease register for South Wales, a total of 86 affected individuals were identified living in the counties of Mid Glamorgan, South Glamorgan and Gwent, giving a point prevalence rate for Huntington's Disease in South East Wales of 6.2/100,000. Only four (4.7%) of these individuals developed their symptoms after the age of 60 years. A subsequent retrospective search of the register identified a total of 33 individuals with clinical evidence of Huntington's disease and whose age of onset of symptoms occurred between the ages of 60 and 77 years. In this group the median time for disease duration from the onset of symptoms was 13 years (range 0.5-25 years), with survival up to age 86 years recorded. Initial symptoms of Huntington's disease included disturbance of gait in 32 individuals; 31 had involuntary movements, and 20 had abnormality of speech. Major psychiatric symptoms were present in only six cases; but approximately a third (ten cases) had symptoms related to impaired cognitive function. Molecular analysis was possible on ten individuals in the series. The expanded CAG repeat sequence in the Huntington's disease gene was found in all cases, with a narrow range of 36-38 repeats, representing the smallest repeats seen in our Huntington's disease group. Our study suggests that Huntington's disease in elderly people causes predominantly motor disturbance at onset with relatively mild disability and a favourable outlook for both independent living and for life expectancy. However, the potential for under-diagnosis in this age group may have considerable genetic consequences, with transmission of the disorder to numerous descendants by the time its hereditary nature is recognized.

Aged↗
PubMed1993

Molecular analysis and clinical correlations of the Huntington's disease mutation.

The genetic mutation underlying Huntington's disease (HD) has been identified as an expansion and instability of a specific CAG repeat sequence in a gene (IT15) on chromosome 4. We have investigated the relation of the phenotype of HD to this molecular defect and assessed the feasibility of HD mutation analysis in diagnosis and prediction. Analysis of DNA from 449 HD patients (351 familial and 98 apparently isolated cases) revealed the mutation in more than 95% of patients from both groups. No molecular difference was found between patients presenting with psychiatric symptoms and those in whom chorea or other motor defects were the principal features; additionally, there was a wide range of age at onset for any specific repeat number, though the small group with juvenile onset and presenting with rigidity showed the largest expansions. The findings suggest that molecular analysis will be an accurate and specific diagnostic test for HD and valuable in presymptomatic detection in individuals at risk. However, such testing will require considerable caution to avoid serious difficulties; the well-established guidelines developed for the use of linked markers in relation to the prediction of HD should continue to be followed, though they will require reassessment in relation to use in diagnosis.

Adult↗
PubMed1993

Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease.

The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.

Adolescent↗
PubMed1993

The isolation of cDNAs within the Huntington disease region by hybridisation of yeast artificial chromosomes to a cDNA library.

Flanking recombination events have defined the Huntington Disease gene candidate region to between D4S10 and D4S98, about 2.2Mb. Because of the large size of the candidate region and the likely large number of genes within it we decided to screen cDNA libraries with probes generated from whole Yeast Artificial Chromosomes (YACs) containing parts of this region. We have thus far used 4 YACs ranging in size from 180kb to 600kb covering 880kb and have isolate 13 cDNA clones, 7 of which are unique. Three of the 13 clones contain parts of the 3' untranslated region of the alpha-adducin gene. One YAC of 600kb could not be purified from two yeast chromosomes, therefore this YAC probe had a net complexity of 1.8Mb. Even so this probe identified a cDNA from the HD candidate region indicating that very large YACs may be used as probes.

Chromosome Mapping↗