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71.
Single-unit activity in primary auditory cortex was studied in unanesthetized, paralyzed cats during the performance of a classical conditioning task. The conditioned stimulus was a 0.5-s white noise (WN) burst paired with tail shock delivered 4.5 s later. Cats habituated to WN without shock served as controls. Overlayed on these tasks was a continuous background of 1/s, behaviorally irrelevant, 100-ms duration tone bursts set to the best frequency and optimal intensity for the particular unit being studied. Spontaneous activity and tone responses following WN were compared with the respective activity preceding WN. The spontaneous or evoked activity of 75% of the cells recorded in the trained animals changed significantly after WN, whereas the activity of 28% of the cells recorded in habituated animals changed. Augmentation and suppression of both spontaneous and evoked activity were found. These results have implications for the encoding of acoustic stimuli in terms of the modulation of lemniscal sensory system activity. 相似文献
72.
Bickerstaff brainstem encephalitis is a clinical syndrome of ophthalmoplegia, cerebellar ataxia, and central nervous system signs and is associated with the presence of anti-GQ1b antibodies. There is a clinical continuum between Bickerstaff brainstem encephalitis and Miller Fisher syndrome. We describe the case of an 11-year-old boy with encephalopathy, external ophthalmoplegia, brainstem signs, and ataxia with raised titers of anti-GQ1b antibodies. He presented following a respiratory illness and had laboratory evidence of recent infection with Mycoplasma pneumoniae. M pneumoniae infection has been associated with both Bickerstaff brainstem encephalitis and Miller Fisher syndrome. This is only the second case in the literature of Bickerstaff brainstem encephalitis with raised titers of anti-GQ1b antibodies described in association with M pneumoniae infection. The patient responded to intravenous immunoglobulin administration. 相似文献
73.
Sisodiya SM Thompson PJ Need A Harris SE Weale ME Wilkie SE Michaelides M Free SL Walley N Gumbs C Gerrelli D Ruddle P Whalley LJ Starr JM Hunt DM Goldstein DB Deary IJ Moore AT 《Journal of medical genetics》2007,44(6):373-380
Background
The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active‐zone protein with important roles in the maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function.Objective
An established paradigm examining the structural and functional effects of mutations in genes expressed in the eye and the brain was used to study a kindred with an inherited retinal dystrophy due to RIMS1 mutation.Materials and methods
Neuropsychological tests and high‐resolution MRI brain scanning were undertaken in the kindred. In a population cohort, neuropsychological scores were associated with common variation in RIMS1. Additionally, RIMS1 was sequenced in top‐scoring individuals. Evolution of RIMS1 was assessed, and its expression in developing human brain was studied.Results
Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests that factors other than RIMS1 mutation were unlikely to explain enhanced cognition. No association with common variation and verbal IQ was found in the population cohort, and no other mutations in RIMS1 were detected in the highest scoring individuals from this cohort. RIMS1 protein is expressed in developing human brain, but RIMS1 does not seem to have been subjected to accelerated evolution in man.Conclusions
A possible role for RIMS1 in the enhancement of cognitive function at least in this kindred is suggested. Although further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest that genetic mutation may enhance human cognition in some cases.A genetic contribution to variation in human intelligence is well established, but the identities of the genes responsible remain elusive. Many mutations are associated with impaired cognition:1 no definite genetic causes of enhanced cognition are established,2 and there are no known cognition‐enhancing “gain‐of‐function” mutations in genes otherwise associated with cognitive impairment. Therapeutic possibilities deriving from the discovery of any such genes or variants are potentially important: cognitive decline reduces the quality of life,3 and low intelligence test scores are associated with increased morbidity and shorter life‐span.4 Accelerated evolution of genes subserving neurodevelopment figures in molecular explanations of the advance of the human nervous system: many of the identified genes regulate brain size and behaviour, some encoding critical synaptic proteins.5To identify genes influencing human brain development and function, including cognitive function, we use a paradigm evaluating cerebral structure and function in individuals with known mutations in genes co‐expressed in the lineage‐sharing eye and brain, ascertained by their obvious ocular phenotype, but in whom a neurological phenotype was not fully appreciated. Using this paradigm, we demonstrated roles for the genes PAX6, PITX2, SOX2 and OTX2 in human brain development, cognitive function and memory.6,7,8,9,10,11We now report on the functional and structural effects of mutation in the eye‐ and brain‐expressed gene RIMS1, through the study of individuals from a family already reported to have retinal dystrophy caused by RIMS1 mutation.12,13 To our knowledge, this is the only family so far reported with such a mutation: the eye phenotype is homogeneous in the family, and has been documented in detail.13 The orthologous murine Rim1α encodes a synaptic active‐zone protein necessary for preserving the normal probability of synaptic neurotransmitter release and for long‐term presynaptic potentiation.14,15Rim1α is also expressed in retinal ribbon synapses.16 Mice lacking Rim1α protein show severely impaired learning and memory.17 In our kindred, RIMS1 mutation (Arg844His) causes a late‐onset dominantly inherited cone–rod dystrophy (CORD7; OMIM 603649), leading to varying degrees of visual loss starting from the third decade onwards.13 Because RIMS1/Rim1α is also expressed in the brain, we hypothesised that this RIMS1 mutation would produce a structural and functional neurological phenotype. 相似文献74.
75.
AM Innes KM Boycott EG Puffenberger D Redl IM MacDonald AE Chudley C Beaulieu R Perrier T Gillan A Wade JS Parboosingh 《Clinical genetics》2010,78(5):424-431
Innes AM, Boycott KM, Puffenberger EG, Redl D, MacDonald IM, Chudley AE, Beaulieu C, Perrier R, Gillan T, Wade A, Parboosingh JS. A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders. Bardet‐Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome‐wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472‐2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population. 相似文献
76.
Our objective was to ascertain the nature of the associations between C-reactive protein (CRP) and cognition, and to examine
how they are affected by gender and obesity. We evaluated 62 females and 63 males between 42 and 82 years of age. There were
20 lean females with a body mass index (BMI) of <25 kg/m2 and 42 overweight or obese females, with BMIs ≥25 kg/m2. There were 14 lean males and 49 with BMIs ≥25 kg/m2. CRP was associated with lower scores on cognitive tests of frontal lobe function among females and these associations were
driven by the overweight/obese female group. In these data no associations between CRP and cognition were found among males.
Obesity-associated inflammation is much more prominent in females and it appears to be associated with cognitive dysfunction,
particularly of frontal lobe tasks. 相似文献
77.
78.
Starr PA Rau GM Davis V Marks WJ Ostrem JL Simmons D Lindsey N Turner RS 《Journal of neurophysiology》2005,93(6):3165-3176
Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 +/- 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 +/-2.5 Hz) and lower than in PD patients (95.2 +/- 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 +/- 1.9 Hz) was lower than in the normal NHPs (69.7 +/- 3.3 Hz) and was indistinguishable from that in PD patients (56.6 +/- 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2- to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity. 相似文献
79.
The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis 总被引:5,自引:0,他引:5
Maheshwar MM; Cheadle JP; Jones AC; Myring J; Fryer AE; Harris PC; Sampson JR 《Human molecular genetics》1997,6(11):1991-1996
Tuberous sclerosis is an autosomal dominant trait in which the
dysregulation of cellular proliferation and differentiation results in the
development of hamartomatous growths in many organs. The TSC2 gene is one
of two genes determining tuberous sclerosis. Inactivating germline
mutations of TSC2 in patients with tuberous sclerosis and somatic loss of
heterozygosity at the TSC2 locus in the associated hamartomas indicate that
TSC2 functions as a tumour suppressor gene and that loss of function is
critical to expression of the tuberous sclerosis phenotype. The TSC2
product, tuberin, has a region of homology with the GTPase activating
protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in
vitro. Here we show that the region of homology between tuberin and human
rap1GAP and the murine GAP mSpa1 is more extensive than previously reported
and spans approximately 160 amino acid residues encoded within exons 34-38
of the TSC2 gene. Single strand conformation polymorphism analysis of these
exons in 173 unrelated patients with tuberous sclerosis and direct
sequencing of variant conformers together with study of additional family
members enabled characterisation of disease associated mutations in 14
cases. Missense mutations, which occurred in exons 36, 37 and 38 were
identified in eight cases, four of whom shared the same recurrent change
P1675L. Each of the five different missense mutations identified was shown
to occur de novo in at least one sporadic case of tuberous sclerosis. The
high proportion of missense mutations detected in the region of the TSC2
gene encoding the GAP-related domain supports its key role in the
regulation of cellular growth.
相似文献
80.
Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis 总被引:7,自引:2,他引:7
Li DY; Toland AE; Boak BB; Atkinson DL; Ensing GJ; Morris CA; Keating MT 《Human molecular genetics》1997,6(7):1021-1028
Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular
disease that affects the aorta, carotid, coronary and pulmonary arteries.
Previous molecular genetic data have led to the hypothesis that SVAS
results from mutations in the elastin gene, ELN. In these studies, the
disease phenotype was linked to gross DNA rearrangements (35 and 85 kb
deletions and a translocation) in three SVAS families. However, gross
rearrangements of ELN have not been identified in most cases of autosomal
dominant SVAS. To define the spectrum of ELN mutations responsible for this
disorder, we refined the genomic structure of human ELN and used this
information in mutational analyses. ELN point mutations co-segregate with
the disease in four familial cases and are associated with SVAS in three
sporadic cases. Two of the mutations are nonsense, one is a single base
pair deletion and four are splice site mutations. In one sporadic case, the
mutation arose de novo. These data demonstrate that point mutations of ELN
cause autosomal dominant SVAS.
相似文献