A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy

Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.     

Abnormal cortical activation during response inhibition in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is a well-known genetic risk factor for schizophrenia. The catechol-O-methyltransferase (COMT) gene falls within the 22q11.2 minimal critical region of the deletion. Brain activity, as measured by functional magnetic resonance imaging (fMRI) during a Go/NoGo, response inhibition task was assessed in adolescents with 22q11.2DS (n = 13), typically developing (TD) controls (n = 14), and controls with developmental disability (DD, n = 9). Subjects with 22q11.2DS were also genotyped for the COMT Met/Val polymorphism. Groups did not differ on task performance. However, compared to both control groups, the 22q11.2DS group showed greater brain activation within left parietal regions. Comparison of brain activation between 22q11.2DS Met and Val subgroups revealed significantly increased activation (Met>Val) in the cingulate but not the dorsolateral prefrontal cortex. These preliminary findings suggest that adolescents with 22q11.2DS compensate for executive dysfunction via recruitment of parietal regions. Further, the COMT Met subgroup of 22q11.2DS may recruit additional cingulate activation for tasks requiring attention and inhibition. 22q11.2DS is a unique model for learning about the deleterious effects of decreased dosage of the COMT gene on brain function.     

Deletions causing spinal muscular atrophy do not predispose to amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably lethal disease resulting from the premature death of motor neurons of the motor cortex, brainstem, and spinal cord. In approximately 15% of familial ALS cases, the copper/zinc superoxide dismutase gene is mutated; a juvenile form of familial ALS has been linked to chromosome 2. No cause has been identified in the remaining familial ALS cases or in sporadic cases and the selective neurodegenerative mechanism remains unknown. Deletions in 2 genes on chromosome 5q, SMN (survival motor neuron gene) and NAIP (neuronal apoptosis inhibitory protein gene), have been identified in spinal muscular atrophy, a disease also characterized by the loss of motor neurons. These genes are implicated in the regulation of apoptosis, a mechanism that may explain the cell loss found in the brains and spinal cords of patients with ALS. OBJECTIVE: To determine whether the mutations causing neurodegeneration in spinal muscular atrophy are present in patients with ALS in whom the copper/zinc superoxide dismutase gene is not mutated. PATIENTS AND METHODS: Patients in whom ALS was diagnosed were screened for mutations in the SMN and NAIP genes by single strand conformation analysis. RESULTS: We found 1 patient with an exon 7 deletion in the SMN gene; review of clinical status confirmed the molecular diagnosis of spinal muscular atrophy. No mutations were found in the remaining patients. CONCLUSION: The SMN and NAIP gene mutations are specific for spinal muscular atrophy and do not predispose individuals to ALS.     

Chromosome 14q11.2‐q21.1 duplication: a rare cause of West syndrome

Proximal duplication of chromosome 14q, including the FOXG1 gene located on 14q12, is a rare condition characterised by developmental delay, dysmorphic craniofacial features, epilepsy, and severe speech delay. Here, we report a patient with West syndrome whose chromosome analysis revealed 14q11.2‐21.1 duplication. The patient was admitted due to infantile epileptic spasms at eight months of age, motor developmental delay, and dysmorphic features. Chromosome and array‐CGH analysis revealed de novo 14q11.2‐21.1 duplication, spanning ～20 Mb (minimal interval chr14:20203610_40396835). The patient was followed up to 13 years of age, and at the last examination was shown to have severe speech delay, seizures, and continuous spike‐and‐wave activity on EEG. The possibility of this chromosomal abnormality should be kept in mind in patients with developmental delay, epilepsy, and hypsarrtyhmia, in the absence of any structural brain lesion or metabolic aetiology.     

Issues & opinion. Sporadic ALS and chromosome 22: Evidence for a possible neurofilament gene defect

ALS is associated with the P2 blood group phenotype. Molecular evidence now shows the gene encoding this antigen to be on the long arm of human chromosome 22 near the newly discovered gene for heavy neurofilament (NF-H). Since an ALS-type condition can be generated in transgenic mice expressing the human NF-H gene, and since the gene for the CNTF-related cytokine leukemia inhibitory factor (LIF) is located adjacent to this gene, it is hypothesized that a defect on the chromosome 22 band region q12 is involved in the pathogenesis of sporadic ALS. © 1995 John Wiley & Sons, Inc.     

Chromosomal translocation t(18;21)(q23;q22.1) indicates novel susceptibility loci for frontotemporal dementia with ALS

A chromosomal translocation t(18;21)(q23;q22) is reported in a patient with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We exclude the physical involvement and silencing of the ALS-linked gene for copper/zinc superoxide dismutase (SOD1) on chromosome 21q22.1. The breakpoints are assigned to sequences flanked by the markers ATA1H06, D18S462, D21S1915, and D21S1898. These critical regions may contain susceptibility loci for FTD associated with ALS.     

Decreased serum angiogenin level in Alzheimer's disease

Background

It has been suggested that Alzheimer's disease (AD) is mediated by pathological angiogenesis. Vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and tumor necrosis factor α (TNF -α) may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization in AD pathogenesis. A few studies on the roles of VEGF in AD have been reported recently. But, the results were inconsistent. Angiogenin, which is suspected to have a similar function as VEGF, however, has not yet been studied in patients with AD.

Objective

This study was performed to investigate the levels of angiogenin and vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptorI (VEGFR I), and vascular endothelial growth factor receptor II (VEGFR II) in serums of patients with AD, to compare their levels with control subjects, and to determine whether serum angiogenin, VEGF, VEGFR I, and VEGFR II levels are associated with Alzheimer's disease (AD).

Methods

Serum angiogenin, VEGF, VEGFR I, and VEGFR II levels were quantified at the time of diagnosis in 20 patients with definite AD, and 18 healthy controls, using a commercial ELISA kit.

Results

Patients with AD exhibited lower serum angiogenin (p = 0.003) and higher VEGF (p = 0.008) levels than control subjects. No difference in serum VEGFR I and VEGFR II concentrations was observed between AD patients and controls. There was a correlation between serum levels of angiogenin and cognitive function (MMSE-KC and CDR) in AD patients.

Conclusion

The increased serum level of VEGF and decreased serum angiogenin level were founded. Cognitive function was correlated with serum levels of angiogenin. Angiogenin may be involved in the pathogenesis of AD. Further study should be needed to evaluate the possibility of serum angiogenin as a biomarker of AD and as a predictor of disease progression.     

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium

Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 markers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 12 years. Evidence for linkage was found with a locus on chromosome 15q14 (ACTC, lod score = 3.46, locus-specific P-value = 0.000014) and suggestive results were observed for another marker on chromosome 7q11.2 (D7S1816, lod score = 2.68, locus-specific P-value = 0.00011). Other interesting findings were obtained with markers on chromosomes 6 and 22, namely D6S1050 (lod score = 2.0, locus-specific P-value = 0.00004) and D22S420 (lod score = 1.91). Nonparametric linkage analysis provided additional support for the role of these loci. Further analyses of these results suggested that the locus on chromosome 15q14 may be implicated in the etiology of BD, whereas the 7q11.2 locus may be relevant for lithium response. In conclusion, our results provide original evidence suggesting that loci on 15q14 and 7q11.2 may be implicated in the pathogenesis of BD responsive to lithium.     

Frontotemporal dementia–amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1–q12.2: genetic, clinical and neuropathological analysis

Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.     

Abnormal myelination in a patient with deletion 14q11.2q13.1

A male carrying an interstitial deletion of chromosome 14, presumably del(14)(q11.2q13), and presenting with abnormal myelination on magnetic resonance imaging is described. The abnormal myelination was evidenced as a high-signal intensity on T(2)-weighted magnetic resonance imaging. The patient had severe neurologic signs, various dysmorphic features, and a marked microcephaly. To our knowledge, this case is the first patient reported with abnormal myelination and a deletion of chromosome 14.     

No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome

OBJECTIVE: Previous studies linking the catechol O-methyltransferase (COMT) functional polymorphism to the specific phenotype in 22q11.2 deletion syndrome (22q11.2DS) have yielded inconsistent results. The goal of the present study was to replicate a recent finding that executive function is higher in individuals hemizygous for the Met allele. METHOD: Thirty-four children and young adults with a 22q11.2 microdeletion, hemizygous for the Val (N=14) or Met (N=20) polymorphism, were tested on measures of executive function, IQ, and memory. RESULTS: No significant differences were detected between Met- and Val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. CONCLUSIONS: These results suggest either a small effect of the COMT polymorphism on executive function in 22q11.2DS or no effect at all. Further research is needed to characterize the implications of hemizygosity of COMT in 22q11.2DS for cognitive function.     

Motoneurons secrete angiogenin to induce RNA cleavage in astroglia

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.     

Systematic Screening for Subtelomeric Anomalies in a Clinical Sample of Autism

High-resolution karyotyping detects cytogenetic anomalies in 5–10% of cases of autism. Karyotyping, however, may fail to detect abnormalities of chromosome subtelomeres, which are gene rich regions prone to anomalies. We assessed whether panels of FISH probes targeted for subtelomeres could detect abnormalities beyond those identified by karyotyping in 104 individuals with Pervasive Developmental Disorders (PDDs) drawn from a general clinical population. Four anomalies were detected by karyotyping, while no additional anomalies were detected by subtelomere FISH or by probes targeted for 15q11.2q13 or 22q11.2 in subgroups of our sample. We conclude that while karyotyping may be more broadly indicated for autism than previously supposed, subtelomere FISH appears less likely to be a useful screening tool for unselected PDD populations.     

Late-onset spinal motor neuronopathy – A common form of dominant SMA

We previously described two Finnish families with a new autosomal dominant late-onset spinal motor neuronopathy that was mapped to chromosome 22q11.2–q13.2. In the current screening study of 43 lower motor neuron disease patients from Finland and Sweden, we identified 26 new late-onset spinal motor neuronopathy patients sharing the founder haplotype. In addition to the main symptoms and signs: painful cramps, fasciculations, areflexia and slowly evolving muscle weakness, new features such as mild bulbar findings, were identified. The disease is relatively benign in terms of life expectancy and rate of disability progression, and it is therefore noteworthy that three patients were initially misdiagnosed with ALS. Significant recombinants in this new patient cohort restricted the disease locus by 90% to 1.8 Mb. Late-onset spinal motor neuronopathy seems not to be very rare, at least not in Finland, with 38 patients identified in a preliminary ascertainment.     

Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder

We describe here familial dyskinesia and facial myokymia (FDFM), a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia. We report a 5-generation family with 18 affected members (10 males and 8 females) with FDFM. The disorder has an early childhood or adolescent onset. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. A candidate gene and haplotype analysis was performed in 9 affected and 3 unaffected members from 3 generations of this family using primers for polymorphic loci closely flanking or within genes of interest. We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine. Our results provide further evidence of genetic heterogeneity in autosomal dominant movement disorders and suggest that a novel gene underlies this new condition.     

The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis

BACKGROUND: Distal myopathies (MPDs) are genetically heterogeneous. Genetic causes within this subgroup of muscle disorders remain largely unknown. An MPD linked to chromosome 14q11-q13 (MPD1) is rare, and to our knowledge, only one family with definitive linkage has been described. OBJECTIVE: To describe the results of clinical and genetic analysis of the second kindred with MPD1. PATIENTS AND METHODS: We have identified a family with an MPD segregating in an autosomal dominant fashion. We tested linkage to previously identified genetic loci on chromosomes 2p, 2q, and 14q. The coding sequence of PABP2 (the polyadenylate-binding protein 2 gene) was analyzed. RESULTS: Every affected individual had selective weakness of foot extensors, with the average age of symptom onset at 20 years. Some patients also had proximal weakness, but none had signs of finger or hand extensor muscle involvement, even in advanced stages of the disease. Two typically affected individuals had signs of idiopathic dilated cardiomyopathy. Genetic analysis detected a tight linkage to chromosome 14q11-q13. Recombination at the telomeric end of the 14q11-q13 locus was found in an unaffected individual who was not considered to be at risk, potentially reducing the locus interval by 2 centimorgans. No mutations in the PABP2 gene were identified. CONCLUSIONS: To our knowledge, our described family is only the second known kindred with a chromosome 14-linked MPD in whom the linkage has been unequivocally established. We did not detect signs of involvement of hand or finger extensors and neck muscles, seen in the original family with MPD1. The degree and frequency of proximal weakness seem to be more prominent than in other patients with MPD1. Haplotype analysis suggests that the gene is located between polymorphic microsatellite markers D14S283 and D14S1034 on chromosome 14q11-q13. The presence of cardiomyopathy in some affected individuals may help in the identification of candidate genes.     

Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. Recently, missense variants in the angiogenin gene (ANG), an angiogenic factor expressed in ventral horn motor neurons that is up-regulated by hypoxia, have been found in ALS patients of Irish/Scottish, North American, Italian, French and Dutch descent. To investigate the role of ANG in the German population, we screened for mutations by sequencing the entire coding region of the ANG gene in a large sample of 581 German ALS cases and 616 sex- and age-matched healthy controls. We identified two heterozygous missense variants, F(−13)L and K54E, in two German sporadic ALS cases but not in controls. Both missense variants are novel and have not been previously found in ALS cases. Our results suggest that missense variants in the ANG gene play a role in ALS in the German population and provide further evidence to support the hypothesis that angiogenic factors up-regulated by hypoxia are involved in the pathophysiology of ALS. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association of ZNF74 gene genotypes with age-at-onset of schizophrenia.

Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia.