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Biomedical subjects

Walter E Kaufmann

Publications and source records attributed to Walter E Kaufmann.

At least 19 recordsLinked to original sources
PubMed2007

Autistic-spectrum disorders in Down syndrome: further delineation and distinction from other behavioral abnormalities.

The present study extends our previous work characterizing the behavioral features of autistic-spectrum disorder (ASD) in Down syndrome (DS) using the Aberrant Behavior Checklist (ABC) and Autism Behavior Checklist (AutBehav). We examined which specific behaviors distinguished the behavioral phenotype of DS + ASD from other aberrant behavior disorders in DS, by determining the relative contribution of ABC and AutBehav subscales and items to the diagnosis of ASD. A total of 127 subjects (aged 2-24 years; mean age: 8.4 years; approximately 70% male), comprising: a cohort of 64 children and adolescents with DS and co-morbid ASD (DS + ASD), 19 with DS and stereotypic movement disorder (DS + SMD), 18 with DS and disruptive behaviors (DS + DB), and 26 with DS and no co-morbid behavior disorders (DS + none) were examined using the aforementioned measures of aberrant behavior. We found that subjects with DS + ASD showed the most severe aberrant behavior, especially stereotypy compared to DS + none and lethargy/social withdrawal and relating problems compared to DS + SMD. Specifically, relatively simple stereotypic behavior differentiated DS + ASD from DS + DB, whereas odd/bizarre stereotypic and anxious behavior characterized DS + ASD relative to DS + SMD and DS + none. Additionally, in a subset of subjects with DS + ASD and anxiety, social withdrawal was particularly pronounced. Overall, our findings indicate that a diagnosis of DS + ASD represents a distinctive set of aberrant behaviors marked by characteristic odd/bizarre stereotypic behavior, anxiety, and social withdrawal.

Adolescent↗
PubMed2006

Social approach and autistic behavior in children with fragile X syndrome.

Social avoidance is a core phenotypic characteristic of fragile X syndrome (FXS) that has critical cognitive and social consequences. However, no study has examined modulation of multiple social avoidant behaviors in children with FXS. In the current study, we introduce the Social Approach Scale (SAS), an observation scale that includes physical movement, facial expression, and eye contact approach behaviors collected across multiple time points. Our findings suggested that social approach behaviors in children with FXS were affected by age, gender, setting, and time spent with an examiner. Selected social approach behaviors were related to autistic behavior. Increased eye contact over the course of a research assessment, in particular, was found to be a strong predictor of lower autistic behavior.

Age Factors↗
PubMed2006

Autism spectrum disorder in Fragile X syndrome: differential contribution of adaptive socialization and social withdrawal.

The present study extends our previous work on characterizing the profile of social behavior abnormalities in boys with Fragile X (FraX) and autism spectrum disorder (ASD) using clinically oriented behavioral rating scales and standardized instruments. The goal was to further distinguish behavioral parameters contributing to the diagnostic classification of FraX + ASD. The study design included two cohorts of boys with FraX (3-8 years), a larger main cohort for cross-sectional analyses (n = 56, 24 with ASD), and a longitudinal subset (n = 30, 11 with ASD) of the main cohort with up to 3 yearly observations. The focus was on the relative contribution of delayed adaptive socialization and social withdrawal, including item components of their corresponding rating instruments, to the diagnosis of ASD in boys with FraX. Using a combination of regression analyses, we demonstrated that: (1) as delayed socialization, social withdrawal is also a correlate of FraX + ASD; (2) items of social withdrawal scales representing avoidance were the main predictors of ASD status, particularly in older boys; (3) adaptive socialization skills reflecting rules of social behavior and recognition and labeling of emotions, linked to verbal reasoning abilities, were selectively associated with FraX + ASD; (4) adaptive socialization is the primary determinant over time of ASD status in boys with FraX; and (5) integrated adaptive socialization-social withdrawal models allow the identification of distinctive FraX + ASD subgroups. Altogether, our findings suggest that two distinct but interrelated social behavior abnormalities, one linked to impaired cognitive processes (delayed socialization) and the second one to disturbance in limbic circuits (avoidance), play a role in the development of ASD in boys with FraX.

Adaptation, Psychological↗
PubMed2005

MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution.

Most cases of Rett syndrome (RTT) are associated with mutations of the transcriptional regulator MeCP2. On the basis of molecular structure, ontogeny, and subcellular and regional distribution, MeCP2 appears to be a link between synaptic activity and neuronal transcription. Integrating data on MeCP2 neurobiology, RTT neurobiology, MeCP2 mutational patterns in RTT and other disorders, histone profiles of relevance to RTT, and genotype-phenotype correlations in RTT, we update here our synaptic hypothesis of RTT. We postulate that MeCP2 dysfunction leads to abnormal brain development through maladjustment of neuronal gene expression to synaptic and other extra-cellular signals, mainly during the critical period of synaptic maturation. RTT phenotype will develop, only if severe MeCP2 dysfunction is present during early neuronal differentiation. Two models are proposed for explaining general and regional neuronal abnormalities in RTT and the phenotypical outcome of MeCP2 dysfunction, respectively.

Animals↗
PubMed2005

Diffusion tensor imaging in schizophrenia.

BACKGROUND: Diffusion tensor imaging (DTI) is a relatively new neuroimaging technique that can be used to examine the microstructure of white matter in vivo. A systematic review of DTI studies in schizophrenia was undertaken to test the hypothesis that DTI can detect white matter differences between schizophrenia patients and normal control subjects. METHODS: EMBASE, PubMed, Medline, and PsychInfo were searched online and key journals were searched manually for studies comparing anisotropy (a measure of white matter integrity) between patients and control subjects. Nineteen articles were systematically reviewed. RESULTS: Though 16 studies found differences, methodological and data differences prevented a meta-analysis. Fourteen studies found reduced anisotropy in patients; two studies found only a loss of normal asymmetry. The region of investigation varied across studies, however, and when the same region (for example, the cingulum) was examined in different studies, as many failed to find a difference as found one. These inconsistencies may be the result of small sample sizes and differences in methodology. CONCLUSIONS: Diffusion tensor imaging has yet to provide consistent findings of white matter abnormalities in schizophrenia. Its potential as a means of examining anatomical connectivity may be realized with the study of larger, more homogenous groups of subjects and with ongoing improvements in image analysis.

Adult↗
PubMed2005

Down syndrome and comorbid autism-spectrum disorder: characterization using the aberrant behavior checklist.

To report on the cognitive and behavioral attributes of 61 children with Down syndrome (DS) and autistic-spectrum disorder (ASD) according to DSM-IV criteria; to determine the utility of the aberrant behavior checklist (ABC) to characterize these subjects for research purposes; and to test the hypothesis that subjects with DS + ASD could be distinguished from their typical DS peers using the ABC. Cross-sectional design. Cases with DS + ASD (N = 61), comparison group of DS + stereotypy movement disorder (SMD) (N = 26) and typical DS controls without behavior problems (N = 44) were ascertained and enrolled sequentially upon presentation to a DS clinic at an academic medical center over a 10-year period from 1991 to 2001. All subjects underwent neurodevelopmental and medical evaluation, and standardized cognitive testing. The parents provided responses to standardized behavioral questionnaires. Cognitive function (IQ) differed markedly across the three groups. The Lethary and Stereotypy subscales of the ABC were highly significant (P < 0.001) in distinguishing the three groups from one another. Within the ASD group differences were apparent by DSM-IV type on the Lethargy subscale, which reached significance, ANOVA (F = 0.002) and t-test (Autism > PDD, P = 0.005; PDD < CDD, P = 0.002). Using a multivariate regression model, the ABC scales alone explained 62% of variance of ASD outcome; addition of demographic variables explained up to 68% of the variance. There is good correlation between DSM-IV criteria for autism and subscales scores on the ABC in subjects with DS. This study demonstrates the feasibility of using the ABC to characterize the neurobehavioral phenotype of a cohort of children with trisomy 21 and ASD for ongoing research purposes.

Adolescent↗
PubMed2005

Histone modifications in Rett syndrome lymphocytes: a preliminary evaluation.

Most cases of Rett syndrome (RTT) are associated with mutations in the coding region of the transcriptional regulator MeCP2. This gene appears to repress gene expression through chromatin conformational changes secondary to histone modifications, mainly histone deacetylation of core histones H3 and H4. There is limited and contradictory information about histone modifications in RTT tissues. The present study intended to provide a preliminary characterization of histone acetylation (AcH3, AcH4) and methylation (MeH3) in RTT, with emphasis on non-selected peripheral cells and molecular-neurologic correlations. We compared 17 females with RTT, 11 of them with MeCP2 mutations, with 10 gender-matched controls in terms of lymphocyte lysate immunoblotting-based levels. We found that immunoreactivities for MeCP2 and AcH3/AcH4 are variable in both control and RTT subjects. Despite this variability, RTT subjects with nonsense mutations showed the expected reduction in C-terminal MeCP2 immunoreactivity. Regardless of MeCP2 levels, both subjects with (RTTPos) and without (RTTNeg) mutations had decreased levels of AcH3. The latter reductions were mainly driven by decreases in levels of H3 acetylated at lysine residue 14 (AcH3K14) and independent of parallel, but milder, decreases in immunoreactivity for MeH3 lysine residues (MeH3K4/MeH3K9). Within our study sample, reductions in AcH3 were correlated with severity of head growth deceleration in the RTTPos group. This contrasted with the lack of significant association between location of MeCP2 mutation and severity of the RTT neurologic phenotype. We concluded that there were distinctive profiles of histone acetylation/methylation in RTT peripheral cells, which reflect pathogenetic mechanisms common to subjects with clinical features of this disorder, regardless of mutation status, and that these patterns may be relevant to neurologic dysfunction in RTT.

Acetylation↗
PubMed2004

Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors.

The present study extends our previous work on social behavior impairment in young males with fragile X syndrome (FraX). Specifically, we evaluated whether the autistic phenomenon in FraX is expressed as a range of behavioral impairments as in idiopathic autism (Aut). We also examined whether there are behaviors, identified as items of the Autism Diagnostic Interview-Revised (ADI-R), that in FraX predispose to or differentiate subjects with autism spectrum disorder (ASD) diagnosis. Finally, regression models were utilized to test the relative contribution of reduced communication and socialization skills to ADI-R scores and diagnoses. A cohort of 56 boys (3-8 years) with FraX was examined in terms of scores on measures of cognition (IQ was a co-variate in most analyses.), autistic behavior, problem/aberrant behavior, adaptive behavior, and language development. We found that, indeed, in terms of problem behavior and adaptive skills, there is a range of severity from FraX + Aut to FraX + PDD (Pervasive Developmental Disorder) to FraX + none. ADI-R items representing "Play" types of interaction appear to be "susceptibility" factors since they were abnormal across the FraX cohort. Integrated regression models demonstrated that items reflecting complex social interaction differentiated the FraX + ASD (Aut + PDD) subgroup from the rest of the FraX cohort, while abnormalities in basic verbal and non-verbal communication distinguished the most severely affected boys with FraX + Aut from the milder FraX + PDD cohort. Models incorporating language, adaptive communication, and adaptive socialization skills revealed that socialization was not only the main influence on scores but also a predictor of ASD diagnosis. Altogether, our findings demonstrate that the diagnosis of ASD in FraX reflects, to a large extent, an impairment in social interaction that is expressed with variable severity in young males with FraX.

Adaptation, Psychological↗
PubMed2004

Longitudinal evolution of unidentified bright objects in children with neurofibromatosis-1.

Neurofibromatosis type-1 (NF-1) is the most common autosomal dominant disorder affecting the central nervous system. Magnetic resonance imaging (MRI) has revealed distinctive T2-weighted hyperintense foci (termed unidentified bright objects, UBOs) which appear to represent spongiform changes in the white matter. Cross-sectional and longitudinal analyses suggest that UBOs disappear over time; however, none of these studies have examined comprehensively these foci. We conducted a quantitative MRI longitudinal study of number of affected regions, number of UBOs per region, and UBO volume per region, in a sample of 12 children with NF-1. We applied semi-automatic morphometric methods and comprehensive statistical approaches, within a detailed anatomical parcellation framework. Our data demonstrate that, despite a similar UBO regional distribution (e.g., prevalent globus pallidus/internal capsule (GP/IC) location), UBO evolution was more complex than previously reported. In some subjects, the total number of UBO-occupied locations demonstrated a decrease between approximately ages 7 and 12 years, followed by a progressive increase during adolescence. This pattern was also found for UBO number and/or volume for all regions, with the exception of the cerebellar hemispheres. This REGIONAL distinction may reflect differences in white matter structure between affected long tract fiber bundles and that of cerebral and cerebellar myelinated fibers. The findings are also discussed in the context of previous MR and behavioral studies. We conclude that studies like the present one, in association with other MR modalities, are necessary to characterize more completely the nature and evolution of UBOs and their role in the cognitive phenotype of NF-1.

Adolescent↗
PubMed2004

Social behavior profile in young males with fragile X syndrome: characteristics and specificity.

The present study characterizes distinctive and specific features of social behavior impairment, termed social behavior profile (SBP), in young males with fragile X syndrome (FraX). Fourteen males with FraX and autism (FraX+Aut), ages 3-8 years, were compared with either 41 FraX boys without autism (Aut), 7 age-matched males with developmental language delay and autism (DLD+Aut), or with 11 boys with non-selected (for language delay) idiopathic autism (IA), on several standardized instruments assessing social behavior and autistic features (i.e., autism diagnostic interview-revised, ADI-R). We found that FraX+Aut subjects displayed more impairment in overall cognition, problem/aberrant behavior, and adaptive behavior than the rest of the FraX cohort, even when individuals with pervasive developmental disorder (PDD) were included in the latter. Compared to both DLD+Aut and IA, FraX+Aut males were less impaired in ADI-R reciprocal social interaction (RECS) domain. However, boys with FraX+Aut were in general comparable to DLD+Aut subjects in problem/aberrant and adaptive behaviors. Based on the contrast between FraX+Aut and non-autistic FraX and DLD+Aut, we were able to identify measures (e.g., child behavior checklist (CBCL) withdrawn subscale) that better define social interaction impairment in FraX. Comparisons with DLD+Aut and IA led to the conclusion that communication impairment (COMM) and stereotypic behavior contribute relatively more to the diagnosis of autism in FraX+Aut. In agreement with recent studies, our data suggest that FraX+Aut, and more generally SBP, is a distinctive subphenotype among boys with FraX, which may share some pathophysiological mechanisms with IA.

Adolescent↗
PubMed2004

Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.

BACKGROUND: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity,is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). OBJECTIVE: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. DESIGN: Clinical, imaging, and genotype/phenotype studies were performed. RESULTS: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1% of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2% of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. CONCLUSIONS: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.

Acute Disease↗
PubMed2004

Asymmetry and gender effect in functionally lateralized cortical regions: a proton MRS imaging study.

PURPOSE: to compare metabolite concentrations and ratios in gray matter regions known for their anatomical/functional asymmetry and evaluate gender effect. MATERIALS AND METHODS: Proton MRS imaging was performed at 1.5 T with TR/TE 2300/280 msec in 20 healthy right-handed subjects (mean age 29.6 +/- 5.3 years, 10 men). Concentrations of N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr), and the peak area ratios NAA/Cho, NAA/Cr, and Cho/Cr were evaluated in hippocampal and parahippocampal gyri, thalamus, insula, Broca's and Wernicke's areas (and corresponding contralateral areas), primary and secondary visual areas, temporal, inferior parietal, cingulate, supplemental motor, dorsolateral prefrontal, and sensorimotor areas. Linear mixed-effects regression models were used for statistical analyses. RESULTS: NAA concentration and NAA/Cho were higher in the left thalamus by 21.9% and 20%, respectively (both P < 0.001). NAA concentration was 13% higher in the region contralateral to Wernicke's area (P < 0.02). No gender differences were found. CONCLUSION: Metabolite concentrations and ratios were symmetric and gender independent in most brain regions, however small hemispheric side differences in the thalamus and in Wernicke's area were found.

Adult↗
PubMed2003

Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study.

To gain insight into the specificity of cerebellar vermian abnormalities reported in autism, we conducted a magnetic resonance imaging (MRI) study of boys with either of two conditions associated with autism, Down syndrome and fragile X syndrome, compared with boys with idiopathic autism and controls. The subjects, ranging in age from 3 to 9 years, included 16 boys with Down syndrome + autism and 11 boys with Down syndrome only; 13 boys with fragile X syndrome + autism and 9 boys with fragile X syndrome only; 10 boys with idiopathic autism; and 22 controls. Diagnosis of autism was based on DSM-IV criteria, confirmed primarily by the Autism Diagnostic Interview. T1-weighted midsagittal MRIs were used to measure midline structures. Intracranial area, reflecting brain size, was significantly smaller in subjects with Down syndrome. Therefore, all vermian measures were expressed as ratios to intracranial area. Analysis of covariance (covarying for age and IQ) demonstrated that posterior vermi (lobules VI-VII and VIII-X) were markedly smaller in both Down syndrome groups and those with fragile X syndrome only, whereas only lobules VI-VII were reduced in idiopathic autism. Factorial analyses of variance tested interactions between autism factor and the diagnosis of Down syndrome or fragile X syndrome. The size of lobules VI-VII/intracranial area was dependent on autism status only in fragile X syndrome, with ratios significantly larger in fragile X syndrome with autism with respect to fragile X syndrome only. We conclude that selective posterior vermis hypoplasia is seen not only in idiopathic autism but also in Down syndrome and some individuals with fragile X syndrome. However, reductions in vermian lobules VI and VII appear to be specific to idiopathic autism, whereas increased size of lobules VI and VII is associated with autism in fragile X syndrome. The latter results are consistent with MRI studies showing lobules VI-VII hyperplasia in a subset of subjects with idiopathic autism and cerebral and hippocampal enlargements in fragile X syndrome.

Autistic Disorder↗
PubMed2003

MeCP2 expression in human cerebral cortex and lymphoid cells: immunochemical characterization of a novel higher-molecular-weight form.

Most cases of Rett syndrome are associated with mutations in the coding region of MECP2. Here we characterized a novel MeCP2 immunoreactivity, initially detected in normal cerebral cortex, by using a panel of MeCP2 antibodies and a combination of immunochemical techniques. We found that a novel higher-molecular-weight form (approximately 100 kDa) of MeCP2 is detected in human frontal cortex nuclear and synaptic fractions and in lymphoid cells. Although in the cortex the higher-molecular-weight form is relatively more abundant than the standard approximately 75 kDa immunoreactivity, in extranuclear locations, lymphocyte lysates show a predominance of the standard 75 kDa band. Lymphoblasts revealed a more complex pattern of MeCP2 expression, with prominent higher-molecular-weight form and both higher-molecular-weight form and 75 kDa MeCP2 immunoreactivities encompassing several closely migrating bands. We also successfully immunoprecipitated both the 75 kDa immunoreactivity and the higher-molecular-weight form MeCP2 from cerebral cortex with a C-terminal antibody and confirmed their identities by immunoblotting with C- and N-terminal antibodies. Our data provide compelling evidence for the existence of a novel MeCP2 molecular form, most likely the result of post-translational modification. Detection in both brain and lymphoid cells suggests an important role for higher-molecular-weight form in MeCP2-dependent processes. The presence of higher-molecular-weight form MeCP2 in postsynaptic fractions indicates a possible involvement in linking synaptic activity and transcriptional repression that, in turn, could play a role in the pathogenesis of Rett syndrome and other neurologic disorders.

Adolescent↗
PubMed2002

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome.

Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). Several research groups have therefore used anatomic magnetic resonance imaging (aMRI) to obtain volumetric measurements of subregions of the frontal lobe in these disorders. Most previous studies have relied on subparcellation methods that utilize callosal landmarks to derive subregions of the frontal lobe. In contrast, we present here an investigation of frontal lobe morphometry in ADHD and TS based on a reliable frontal subparcellation protocol that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules based on prior functional studies. This highly reliable procedure subdivides the frontal lobe into five major modules: prefrontal, premotor, motor (precentral gyrus), anterior cingulate, and deep white matter. The first four modules are also segmented into gray and gyral white matter compartments. The protocol was applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD, 13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found volumetric reductions in both the gray and white matter of the prefrontal cortex. These findings, in conjunction with previous reports on basal ganglia abnormalities, suggest that prefrontal-striatal pathways may be anomalous in ADHD. In TS, we found volumetric decreases in the left deep frontal white matter. Decreases in deep white matter suggest the presence of abnormalities in long associational and projection fiber bundles in TS. The findings of this study both confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating that the reliable parcellation method presented has the potential of increasing our understanding of the role of the frontal lobe in developmental and psychiatric disorders.

Adult↗
PubMed2002

Smaller prefrontal and premotor volumes in boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit/hyperactivity disorder (ADHD) have been limited by use of callosal rather than sulcal/gyral landmarks in defining cerebral lobes and functionally relevant sublobar regions (e.g., prefrontal cortex). We present an investigation of cerebral volumes in ADHD using a Talairach-based approach that uses cortical landmarks to define functionally relevant regions. METHODS: Volumes were compared between groups of 12 boys with ADHD and 12 age- and gender-matched control subjects, using a series of multiple analyses of variance. RESULTS: Boys with ADHD had (on average) 8.3% smaller total cerebral volumes. Significant reductions in lobar volumes were seen only for the frontal lobes. Within the frontal lobes, a reduction was seen in both gray and white matter volumes, with some evidence suggesting lateralization of these findings: reduction in frontal white matter volume was specific to the left hemisphere; there was a bilateral reduction in frontal gray matter volume but more so in the right hemisphere. Subparcellation of the frontal lobe revealed smaller prefrontal, premotor, and deep white matter volumes. CONCLUSIONS: Findings suggest that ADHD is associated with decreased frontal lobe gray and white matter volumes. More than one subdivision of the frontal lobes appears to be reduced in volume, suggesting that the clinical picture of ADHD encompasses dysfunctions attributable to anomalous development of both premotor and prefrontal cortices.

Adolescent↗
PubMed2002

Molecular phenotype of Fragile X syndrome: FMRP, FXRPs, and protein targets.

Fragile X syndrome (FraX) is one of the most prevalent genetic causes of mental retardation. FraX is associated with an unstable expansion of a polymorphism within the 5' untranslated region of the FMR1 gene. The main consequence of this mutation is a reduction in the levels of the gene product (FMRP). FMRP is an RNA-binding protein with multiple spliced variants (isoforms) and high levels of expression in a variety of tissues, including neurons. In the latter cells, it is localized not only to the perikaryon but also to dendrites and dendritic spines. FMRP belongs to a family of proteins that includes the Fragile X Related Proteins or FXRPs. FXRPs share high homology in their functional domains with FMRP, and also associate with mRNA and components of the protein synthesis apparatus. However, FXRPs do not have the same temporo-spatial pattern of distribution (and other properties) of FMRP. Immunochemical assays have confirmed that a functionally uncompensated FMRP deficit is the essence of the FraX molecular phenotype. Here, we report our preliminary study on FXRPs levels in leukocytes from FraX males. By immunoblotting, we found that a marked reduction in FMRP levels is associated with a modest increase in FXR1P and no changes in FXR2P levels. The consequences of this reduced FMRP expression on protein synthesis, in other words, the identification of FMRP targets, can be studied by different molecular approaches including protein interaction and proteomics methods. By two-dimensional gel electrophoresis, we showed that in FraX leukocytes there is a defect in acetylation that involves prominently the regulatory protein annexin-1. Extension of current studies of the molecular phenotype to more brain-relevant tissue samples, a wider range of proteomics-based methods, and correlative analyses of FMRP homologues and FMRP targets with multiple behavioral measures, will greatly expand our understanding of FraX pathogenesis and it will help to develop and monitor new therapeutic strategies.

Animals↗